Determination of Medical Causation, by DH Marks

EVALUATION OF CAUSATION IN A CASE INVOLVING DRUGS. 

in: Drug Injury: Liability, Analysis and Prevention, 3rd and 4th Editions, O’Donnell JT editor. L&J Publications, 2012-2022

https://books.google.com/books/about/Drug_Injury.html?id=EB00rD8AqaYC

Donald H. Marks MD PhD and James T. O'Donnell PharmD MS FCP    June 2, 2022

 

Drug Injury V

 

Synopsis

15.1 What is Causation?

15.2 Importance of Establishing Causation

15.3 Definitions

15.4 Degree of Adverse Effects Relate to Intervention

15.5 Methodology to Investigate Causation

15.6 Structured Algorithms for Determination of Causation

         A. Hill Criteria—Expanded Discussion

                  1. Strength of association

                  2. Consistency of results

                  3. Specificity

                  4. Temporal relationship

                  5. Dose response

                  6. Biological plausibility

                  7. Biological coherence

                  8. Experimentation

                  9. Analogy

15.7 Comments on the Individual Riddell Criteria for Causation

15.8 Daubert and the Evolution of Causation

15.9 Does Causation Need to be Established Before a Warning is Given?

15.10 What are the qualifications needed to Give Causation opinions?

15.11 Case reports demonstrating application of causation principles

15.12 Summary

Endnotes

 

15.1 What is Causation?

Medical causation is the determination of whether an adverse effect was caused by the use of a medication, biological, vaccine, device or procedure, all of which are generally referred to as “treatments.” An adverse effect refers to an untoward physical sign, symptom, abnormal assessment (lab value, vital sign, ECG, etc.), or cluster of signs, symptoms, abnormal assessments within the definition of FDA reg 21 CFR.¹ Physical signs can include fever, hypertension, weight loss or other physical findings. A symptom can include any complaint from a patient, including nausea, headache, abdominal pain or others. A medication can refer to any FDA-approved prescription drug or to an over-the-counter preparation. Biologicals refer to prepared synthetic materials of living origin. Vaccines are preparations designed to induce a protective or therapeutic immune response. Medical devices include both large units (MRI) and miniature units (intravascular stents).

 

When determining whether there is causal relatedness between a treatment and an adverse event, one must follow standard, consistent and universally accepted rules of causation. It must always be kept in mind that correlation does not imply nor prove causation. Recent examples of faulty correlation include the supposed relatedness between HRT and coronary heart disease (HormonE Therapy and Heart Disease, American College Obstetrics Gynecology). Also note that even if the logical basis for supporting causation is not reasonable, the causation still may exist.

 

 

15.2 Importance of Establishing Causation

Patients who receive a treatment for an illness generally can be expected to have, as a result of their illness, physical signs and symptoms as manifestations of their illness. As a general statement, all treatments also can cause their own array of physical signs and symptoms separate from the underlying illness being treated, and these new signs and symptoms are referred to as adverse effects. This illustrates the crux of medical causation’s difficulty—distinguishing adverse effects of treatments from signs or symptoms of the underlying illness they are being given to treat.

       This problem is illustrated by the medication Lotronex (alosetron, Glaxo Wellcome), an antagonist of the 5-HT3 (serotonin) receptor. Lotronex was indicated for the treatment of severe, chronic, diarrhea-predominant irritable bowel syndrome (IBS) in women for which conventional therapy had failed. IBS patients can typically present with a wide range of GI symptoms and signs. Unfortunately, Lotronex can act both as a serotonergic drug and as a Serotonin Reuptake Inhibitor (SRI). Serotonin is a potent neurotransmitter (NM) which activates a muscle at the neuromuscular (NM) endplate. The intensity and duration of the muscle activation is directly related to the concentration of serotonin at the NM end plate. Lotronex mimics serotonin at the active receptor and blocks serotonin resorption, thereby causing an inordinately high level of serotonin activity in the GI NM endplate. This high serotonin level can be associated with severe vasoconstriction and ischemia.²

       Elevated serotonin levels are known and accepted causes of many of the serious side effects of Lotronex, including obstruction, perforation, impaction, toxic megacolon, and secondary ischemia. This led to the quandary that the signs and symptoms of an adverse effect³ from the medication Lotronex, which could have warned of an adverse event (AE) and led to the drug’s discontinuation, were similar to the not unexpected signs and symptoms of the underlying disease (IBS) being treated. Ultimately this difficulty of use, not uncommon for a number of medications, led to the removal of Lotronex from the market.

       Another significant causation determination of a serotoninergic adverse effect  is the development of depression leading to suicidal ideation from use of metoclopramide, a drug used to treat GI symptoms such as acid reflux and nausea.⁴ This drug has both central (nausea) and peripheral (gastric motility) actions, is an antagonist of dopamine, and sensitizes gastric smooth muscle to the effects of acetylcholine stimulation. Metoclopramide (Reglan) has a varied CNS effect, including drowsiness, extra pyramidal syndrome (dystonias, akathisia), depression, dizziness and insomnia. It should not be surprising that a drug with antipsychotic efficacy, and which can cause akathesia, may cause an increased risk of suicide, as is pointed out in the prescribing information for Reglan.  The establishment of the causation risk led to significantly decreased clinical use.

 

15.3 Definitions

In general, both the pharmaceutical industry and the regulatory bodies use the same definitions for adverse events (AE) and effects. The FDA's definitions for these terms are included in 21CFR.¹ Providers who observe a potential AE and patients who experience an AE can use different definitions or meanings of commonly used terms such as causation, probable, possible, severe, and serious. The potential for imprecise use of terms can lead to some confusion when AEs are reported to regulatory agencies. Variations in description are just one of several reasons why primary MedWatch reports need to be thoroughly evaluated, rather than simply tabulated. MedWatch reports can supply critical information on unsuspected, previously unreported adverse events (e.g., heart valve thickening and pulmonary hypertension after Fen-Phen), or an incidence rate which is greater than previously known (rhabdomyolysis with statins). The following are definitions of some commonly used terms, which are found in 21CFR 312.32 (revised as of April 1, 2015:

 

.     

.     

.

1. Adverse events: “any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related.”

2. Life-threatening adverse events or suspected life-threatening adverse reactions: "An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death.”

3. Serious adverse event: Per the FDA, “An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.”

15.4 Degree of Adverse Effects Relate to Intervention

 

Causation – causal relatedness of a drug to an AE - can be rated as : definitely, probably, possibly or unrelated to the treatment. Each of the degrees of relatedness has definite meanings, and their structured and consistent application is important for patients receiving the medication and for prescribing physicians. These terms are mentioned in 21CFR¹ and their use is consistent throughout the pharmaceutical industry, the FDA, CDC, ICH and WHO. Under the revised  reporting FDA requirements (21CFR 312.32) for adverse events (AEs) which occur in an investigational new drug application (IND), the definition of “suspected adverse reaction” imposes a greater burden on sponsors to determine whether the drug caused the event, which would transform the temporally related  adverse reaction from an adverse event to an adverse effect. A wider application to these revised rules and definitions should be anticipated by the sponsor when reporting.

 

In an ideal world, it would be helpful if all observed potential adverse events were reported to the drug manufacturer, or to the FDA, via MedWatch forms, and through established reporting channels to the FDA. This would include all suspected adverse reactions seen as part of clinical use and also within clinical research protocols.  In actual practice, less than 10%, and possibly as few as <1% of all suspected adverse reactions are reported. Those of low seriousness and those well-known are probably reported the least, whereas those of high potential seriousness, new or different could be expected to be reported. There are strict expectations on the part of the regulatory agencies for reporting of AE by drug manufacturers, but in practice these are not always followed. ⁵ Further, manufacturers maintain their own adverse event reports database, which is not available for inspection to the public and in general not to the regulatory agencies.

 

       The determination of a degree of causation must occur within structured guidelines,⁶ such as those of Koch,⁷ Hill^8,9 or Riddell.¹⁰ Some degree of flexibility is required, as circumstances demand. A practical definition scheme for assessing the degree of causality is as follows:

 

Unrelated:

The adverse event is clearly due to extraneous causes (e.g., underlying disease, environment).

 

Unlikely (must have 2):

The adverse event:

1)    does not have temporal relationship to intervention,

2)    could readily have been produced by the subject’s clinical state,

3)    could have been due to environmental or other interventions,

4)    does not follow a known pattern of response to intervention,

5)    does not reappear or worsen with reintroduction of intervention.

 

Possible (must have 2):

The adverse event:

1)    has a reasonable temporal relationship to intervention,¹¹

2)    could not readily have been produced by the subject’s clinical state,

3)    could not readily have been due to environmental or other interventions,

4)    follows a known pattern of response to intervention.

 

Probable (must have 3):

The adverse event:

1)    has a reasonable temporal relationship to intervention,

2)    could not readily have been produced by the subject’s clinical state or have been due to environmental or other interventions,

3)    follows a known pattern of response to intervention,

4)    disappears or decreases with reduction in dose or cessation of intervention.

 

Definite (must have all 4):

The adverse event:

1)    has a reasonable temporal relationship to intervention,

2)    could not readily have been produced by the subject’s clinical state or have been due to environmental or other interventions,

3)    follows a known pattern of response to intervention,

4)    disappears or decreases with reduction in dose or cessation of intervention and recurs with re-exposure.

 

For the purposes of  21CFR312.32, a Definite Adverse Event is equivalent to an (known) Adverse Reaction.  A Probable or Possible Adverse Event falls within the FDA definition of Suspected Adverse Reaction until causation can be established: “any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, "reasonable possibility" means there is evidence to suggest a causal relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.”

 

 

       Under the revised  reporting FDA requirements (21CFR 312.32) for AEs which occur in an IND, the relationship of “unknown” is not an option for causality of serious adverse events (SAEs). This creates a   greater burden to establish a causal relatedness.

 

15.5 Methodology to Investigate Causation

Signs or symptoms associated with both regulated treatments can be observed in any phase of development ranging from clinical trial (before a drug is on the market), through initial marketing, up to many years thereafter. Clinical studies beyond the initial and characteristically small Phase I study are designed primarily to demonstrate efficacy—safety data beyond phase i studies is then collected as a secondary parameter. Clinical studies, which can be conducted in a randomized, blinded or non-randomized, non-blinded setting, are varied in their design, and strongly influenced by the disease studied, the drug, and the types of information sought (safety, dosing, efficacy, disease-specific). It is for these reasons that referring to the Randomized Clinical Trial (RCT) as the gold standard for demonstrating causation is overly simplistic and deceptive. Important safety data which has allowed the discovery of new counter indications for already-licensed drugs, and caused the removal from market of others, has even come from a few cases presented in collected case series.^12-14

 

Many clinical trial designs compare newer therapies against placebo. Several advances in clinical trial design have the potential to increase the relevance of trial results to real-world settings. Head-to-head comparisons may incorporate non-inferiority, factorial and crossover designs. The meta-analysis of multiple studies can yield important conclusions not available via single studies, because of limitations on sample sizes, not completely comparable study designs (such as differences in the patient populations) and other features.

 

       Some of the structured settings in which adverse effects can be evaluated include:

 

Randomized Clinical Trial (RCT)- In a RCT, efficacy is almost always the primary parameter, in which case safety is collected as a secondary parameter. An example would be adverse effects which are collected during the efficacy trial of an antihypertensive medication. Data can be collected actively (for example, actively questioned for, and data collected in case report forms), or passively collected, (as when patients volunteer information on adverse effects about which they are not actively questioned).

 

Epidemiologic studies—non-randomized, non-blinded studies which can collect incidence and prevalence data on adverse events in a specific population.

 

Case-controlled studies—patients who exhibit an adverse event are matched with multiple demographically similar but non-exposed patients.^15-17

 

Individual case reports¹⁸ or series—physicians (used here as a general term to include other healthcare providers) publish their observations of novel, unreported adverse effects in individual patients (cases) or groups of patients (series).

 

Network meta-analysis : Network meta-analysis, ¹⁹ can combine direct and indirect evidence together and can compare multiple treatments with each other. Observational data may include disease registries, administrative claims data and electronic medical records. These varied data can be pooled and linked across these data sources, and newer epidemiologic and analytic methods can provide more valid inferences regarding optimal treatment regimens.

 

 

15.6 Structured Algorithms for Determination of Causation

Koch was perhaps the first to set down rules of causation, albeit not for adverse events.⁷ The famous Koch postulates were designed to demonstrate whether a disease was caused by an infectious organism. Some have attempted to adapt Koch’s postulates from infectious disease to drug AE causation, but this has generally been unsatisfactory.

 

       Koch’s Postulates:

1)    The suspected agent must be isolated from a patient with the disease in question.

2)    The agent must be grown in the laboratory in pure culture.      

3)    The isolated agent, grown in pure culture, when infected into a healthy host produces exactly the same clinical disease.

4)    One is able to isolate the same infective organism from the newly diseased person.⁷

 

       Not only are Koch’s postulates not useful for determining AE causation for medications, they are also not practical for many diseases, including HIV (intentional application of the third postulate). In contrast, other criteria, such as those defined by Hill and Riddell, are well-suited for drug adverse causation.

       With a set of eight or nine rules, Hill and also Riddell established systematic methods for evaluating potential drug adverse effect causation. Not all of their rules need to be met for causation to be established, and some are more important than others. One of the first rules to meet is temporality, for it is obvious that symptoms of a putative adverse event which occur before the introduction of a treatment could not have been caused by the treatment. However, the symptom or symptom complex, even if pre-existing, can be exacerbated by the introduction of the medication.

 

             Hill Criteria ²⁰                     Riddell Criteria

Hill Criteria17	Riddell Criteria
Strength of association Consistency of results Specificity Temporal relationship Dose response Biologic plausibility Biologic coherence Experimentation Analogy	Temporal eligibility Latent period Exclusion De-challenge Re-challenge21,22 Singularity of the drug Pattern Drug identification

 

 

A. Hill Criteria—Expanded Discussion.  See Sec 15.7 for more details

 

1. Strength of Association

       A strong association gives support to a causal hypothesis. A weak association requires other information but can be equally as important.

 

2. Consistency of Results

       Repeated findings in different populations and different settings.

 

3. Specificity

       Strengthens confidence in association. Lack of specificity does not rule out causation.

 

4. Temporal Relationship

       Required: exposure must come before disease.

 

5. Dose Response

       Increased dose = increased risk. This holds true for both drugs and for vaccines.

 

6. Biological Plausibility

       Known mechanism not required. For example:

 

Cigarettes and lung cancer

Asbestos and lung cancer

Fen-Phen and valvular heart disease and PPH

 

7. Biological Coherence

       Does not conflict with what is known.

 

8. Experimentation

       RCT is close to experimentation. Removal or reduction of exposure reduces disease. Challenge—de-challenge—re-challenge.

 

9. Analogy

       Similarities with other like exposure. For example:

 

Aminorex and PPH

Ergot drugs and VHD

 

       All of these systems for determination can be simplified in an algorithm-based analysis:

 

1.    Temporal relatedness

2.    Known or reported AE of medication

3.    Presence of concurrent illnesses or medications which could present similarly

4.    Challenge—de-challenge—re-challenge

 

15.7 Comments on the Individual Riddell Criteria for Causation  ^21,22

Temporal Eligibility: As previously discussed, an effect must occur after a treatment in order to establish causation. The effect should not occur too long after the treatment. Inevitably, the question becomes: how long is too long? Regardless of the context, this question, asked without accompanying details, can only have one answer: it depends. Some drugs, such as PCP and Lariam, are known to have neuropsychiatric adverse effects that can last for years after the drug was last taken. Gynecomastia develops only after months of repeated use of  risperidone. Autoimmune or neurologic adverse effects of vaccines can be delayed months after administration. ^23,24

 

       Latent Period: Although the closer the interval between the introduction of the treatment and the adverse effect the better, a long latent period can still be consistent with a causal relatedness. Some adverse effects can have immediate action or a latent period in seconds, such as immediate hypersensitivity reactions. Other adverse effects are more subtle, although equally lethal, and with a longer time delay between exposure and AE, such as liver toxicity from acetaminophen.

       Exclusion: It is important to rule out the effect of concurrent medications or underlying medical conditions such as an alternative hypothesis. Liver enzyme elevations in a diabetic patient with underlying fatty liver, and simultaneously taking a statin for hyperlipidemia, can be a challenge for determination of causation. Regardless, with careful attention to the timeline and details, even in such cases, a determination can be made.

       Challenge: The disappearance or improvement of an adverse event after the withdrawal of the treatment is a positive indication of relatedness. Adverse events can however persist after the treatment is withdrawn, which indicates either that there was no relatedness, or that the adverse effect causes persistent injury.

       Re-challenge: Reintroduction of a treatment which is again associated with the same or similar adverse event is a good indication of causation. If the adverse event does not reappear, this can be a sign of lack of causation, but may also indicate the development of tolerance. Of course, since the potential association in the first place may prevent the reintroduction of the suspect treatment, this is not always possible to see.

       Singularity of the Drug: It is important to determine whether there is something unique about the adverse reaction experience that is not consistent with any other drug taken or any existing disease condition. Even when a supposed unique adverse reaction is noted (e.g., heart valve thickening and pulmonary hypertension with FenPhen), careful investigation can show that a pharmacologically similar medication is known to cause similar adverse effects.

       Pattern: It is important to determine whether similar adverse effects have been described in the literature with the treatment in question or by another medication in the same therapeutic class. A characteristic morphologic pattern in a target organ may suggest an association with a particular drug or group of drugs. For example, “Pseudo-tumor cerebri with hypervitaminosis” provides a literature precedent, and a biological plausibility for similar neurologic injury with Accutane.

       Drug Identification: Identification of the causative agent is of major utility in toxicity and overdose cases. In some cases, such as over-the-counter ephedra associated with intracranial hemorrhage, there may be neither a package insert nor an established laboratory procedure for measuring blood level concentration. It is important to take into account drug metabolism, as it may affect the drug level detected. In some cases, for example with vaccines and biologicals, quantitative determination is not possible, and demonstration of an immune response will suffice.

 

15.8 Daubert and the Evolution of Causation ^25,26

The accurate determination of causation is a crucial part of every investigation of an adverse effect. Causation can determine whether a treatment receives a marketing authorization, whether a treatment is withdrawn from market, and if the AE frequency will be reported in the accompanying labeling (which has a great influence on the

 

competitive market position). The Daubert ruling (Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579, 113 S.Ct. 2786, 125 L.Ed.2d 469, 1993) set the stage for the Federal Rules of Evidence,²⁷ which is the standard for admitting testimony about scientific evidence.  Many, if not most, expert reports concerning causation can expect to have a Daubert challenge over scientific validity. The United States Supreme Court upheld the trial court’s exclusion of evidence in the Daubert case, giving as part of its opinion, four criteria that the trial judge should consider in determining if evidence should be admitted:

 

1.    The theory’s testability,

2.    whether it “has been a subject of peer review or publication,”

3.    the “known or potential rate of error,” and

4.    the “degree of acceptance” within the relevant scientific community. 

 

       The court stressed that this analysis was intended to be flexible, with the trial judge determining how and whether the factors applied in a given case. Although not comparable to the Hill or Riddell criteria, they are just as important, and determinations of causation, while not needing to address all criteria, need to be consistent with them. Any inconsistencies should have a logical and factual basis.

       Daubert v. Merrell Dow Pharmaceuticals, Inc., 43 F.3d 1311, 1317 [9th Cir., 1995] expanded on these rules, listing the following as important considerations:

 

1.    The cases versus controls must have a relative risk or odds ratio of ≥ 2.0 .

2.    The data must be from double or triple-blind clinical trials.

3.    The evidence cited should be from relevant peer-reviewed scientific journals.

4.    Challenge/de-challenge/re-challenge studies are useful in suggesting causation.

5.    Perform or cite epidemiological studies with adequate samples, controls, and appropriate statistical analyses.

6.    Theories or methods utilized should be generally accepted in the relevant scientific community or discipline.

7.    The investigator must make every effort to account for or rule out alternative explanations of the outcome.

8.    Testimony by scientific experts should be non-litigation driven.

9.    Purported outcome effects should be from similar purported causes.

 

Each of these criteria is briefly commented on and explained as follows:

 

1.    Cases versus controls with a relative risk or odds ratio of ≥ 2.0 is a relative and arbitrary standard and not applicable to all conditions, such as idiosyncratic reactions.

2.    Blind, randomized, clinical trials are in general supported by drug companies, to demonstrate efficacy as a means to achieving licensure. Safety data is collected as a secondary parameter.

3.    Even evidence cited from relevant peer-reviewed scientific journals can be questionable. Ghost writing is a common practice in research supported by the pharmaceutical industry. There also have been a number of recent examples of scientific falsification of data, questionable methods and conflict of interest in several prominent peer-reviewed medical journals.

4.    Challenge/de-challenge/re-challenge studies are useful in suggesting causation.

5.    Cite epidemiological studies with adequate samples, controls, and appropriate statistical analyses. There are many instances where the RCT is not appropriate to evaluate a causal relatedness, including:

a.    the difficulties in definition of the population to be studied,

b.    the large sample size needed to detect an event of low incidence (such as suicide, suicide ideation or homicide), and

c.    the bias introduced by employing multiple investigators in order to generate a large sample size.²⁸

       In these cases, an alternative study design, such as challenge-rechallenge, has the potential to better determine whether or not a drug effect is present. These alternative study designs do employ components of the RCT, but can remove bias inherent in epidemiologic studies, view patients at higher risk from a wide variety of sources, and employ objective experimental measures to clarify patient selection, diagnostic, and response parameters.

6.    Theories or methods utilized should be generally accepted in the relevant scientific community or discipline. This is always important, but not all physicians in all cultures and localities agree on the existence, importance or cause of some diseases.

7.    The investigator must make every effort to account for or rule out alternative explanations of the outcome. However, a drug may be a proximate cause without being the proximal cause, and still be causal. A drug may be a necessary (that without which not) condition without being a sufficient (the only) condition. “Ruling out” is not always possible. Further, alternative explanations can still exist.

8.    Testimony by scientific experts should be non-litigation driven. This is important as a demonstration of honesty and objectivity; however many if not most experts have ties to one side of the issue or another, and are compensated for their expert opinions. Applying these criteria to FDA Advisory Committee membership, very few experts would be able to serve.

9.    Purported outcome effects should be from similar purported causes. No comment is necessary.

 

15.9 Does Causation Need to be Established Before a Warning is Given?

This is an area of concern for the pharmaceutical industry, for the prescribing clinician and for the patient. The FDA gives guidance on this issue in 21CFR 201.57. This section provides specific requirements on the content and format (warnings) for human prescription drugs. Section (e) states:

 

e. Warnings: Under this section heading, the labeling shall describe SAE and potential safety hazards, limitations in use imposed by them, and steps that should be taken if they occur. The labeling should be revised to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug, a causal connection need not have been shown.

 

Key points that can be taken from 21CFR 201.57 are:

 

1.    The FDA regulations provide a broad duty to warn: “all serious and potential.” The FDA threshold is not proven causation, but as soon as an “association” is detected. This explains why it states, “a causal connection need not have been shown.”

2.    The duty to warn is also a continuing duty to amend and revise: “…as soon as there is…” The duty to warn is placed on the manufacturer, not on the FDA: Warnings for prescription drugs are typically directed to prescribing physicians, but there are also occasions where warnings must be made directly to the consumer.

 

15.10 What are the Qualifications needed to Give Expert Causation Opinions?

 

Thames and Martin address the topic, Pharmacologist as an Expert Witness, in the context of Daubert applications in pharmaceutical cases²⁹ They write, "…It is commonplace for an expert pharmacologist to educate a jury by explaining a chemical's or a drug's properties and how it works. Expert pharmacologists are sometimes also used to demonstrate that the information available to a pharmaceutical company should have resulted in an additional or heightened warning. A number of courts have allowed pharmacologists to offer expert opinions related to causation wherever the opinion is based on reliable data and methodology."  They go on to state, "In federal court, expert testimony is admissible if offered by a proffered witness 'qualified as an expert by knowledge, skill, experience, training, or education (Fed.R.Civ.Proc. 702). Provided this standard is satisfied, the expert need not hold an advanced degree in pharmacology to offer an expert opinion on an aspect of pharmacology.  Interestingly, the article highlights the Daubert challenges to the admissibility of James T. O'Donnell PharmD's testimony. "One man has almost single-handedly been involved in the decisions constituting the case law in this area. Courts in at least 11 cited cases now have considered whether James O'Donnell Pharm.D., is qualified to testify that either (1) a given warning was inadequate; or (2) a drug is pharmacologically capable of causing a particular effect."  Issues raised in opposition have been that O'Donnell is neither an M.D. nor does he possess a graduate degree in pharmacology.  It is noted, however, that O'Donnell is a Diplomate of the American Board of Clinical Pharmacology.³⁰ The authors note that a few courts have found O'Donnell not qualified, other courts (a majority) have allowed O'Donnell to offer both causation and adequacy of warning expert opinions, finding that his qualifications and background do not, in and of themselves prevent him from offering admissible expert testimony at trial³¹ One opinion (Ashman) stated, "A person with a doctorate in pharmacy can be qualified as a medical expert".

With reference to the standards and qualifications for a physician serving as a medical expert for medical malpractice cases, the AAFP (2004 ) provides the following guidelines ³²:

 

“It is the responsibility of the physician expert witness in a medical liability case to present complete and unbiased information with which the trier of fact can ascertain whether the defendant was medically negligent and whether, as a result, the plaintiff suffered compensable injury and/or damages. The physician expert witness should be aware that transcripts of depositions and courtroom testimony are public records.

 

The physician expert witness should not become an advocate or a partisan during the trial and, to the extent possible, the testimony presented should reflect the generally accepted standards within the specialty or area of practice about which the expert witness is testifying. When there is no generally accepted standard of practice or when the expert witness presents testimony that is contrary to the generally accepted standard, the expert witness should clearly identify that fact, as well as the basis for the opinions expressed. Ideally, both the defense and the plaintiff should have at least one witness in the same specialty as the defendant physician.

 

Prior to testifying, the physician expert witness should become familiar with the facts of the case and the medical standard at issue and should review and understand both the current concepts and practices related to that standard as well as the concepts and practices related to that standard at the time of the occurrence which led to the lawsuit.

 

Compensation to physicians who testify as expert witnesses should be reasonable and commensurate with the time and effort involved in fulfilling the physician's responsibilities as an expert witness. The acceptance of fees that are disproportionately high relative to the time and effort involved may be interpreted as influencing testimony and should be avoided. Under no circumstances should a physician accept compensation for serving as an expert witness when payment of the compensation or the amount of the compensation are contingent upon the outcome of the case.”

 

The AAFP also comments on what should be the minimal qualifications of medical experts for medical malpractice cases :

 

1.       The physician expert witness must have a current, unrestricted license to practice .

 

2.       The physician expert witness should be fully trained in the medical specialty or area of practice about which he or she is testifying.

 

3.       The physician expert witness must have current clinical experience in the medical specialty or area of practice about which he or she is testifying and during the two-year period immediately preceding the occurrence which led to the lawsuit, such person must have been actively engaged in clinical practice in the medical specialty or area of medicine about which he or she is testifying.

 

4.       At least one physician expert witness for the plaintiff and one physician expert for the defendant should be in the same clinical specialty as the defendant physician.

 

Similar but less  detailed guidelines are offered by the AMA (Opinion 9.07 - Medical Testimony, Dec 2004) ³³

 

15.11  CASE REPORTS DEMONSTRATING APPLICATIONS OF CAUSATION PRINCIPLES

 

Treaters, retained experts (physicians, pharmacologists, clinical pharmacists, and toxicologist) are frequently tasked with determining whether or not a drug caused an alleged injury, as well as whether or not the treater (physician, pharmacist, nurse) complied with the applicable standard of care.  The following case reports are presented as examples of determinations of causation.

      

Discussion Case A. Acyclovir Overdose – Pharmacist Recommended Overdose

                             FACTS OF THE CASE

 

George Patient (“Mr. Patient”) presented to Dr. his physician with complaints of a rash on his trunk on 11/20/15.      Mr. Patient was anephric, meaning without kidney function, and had been undergoing hemodialysis three times weekly for a sustained period of time secondary to bilateral nephrectomies. His physician was aware of  Mr. Patient’s lack of kidney function on 11/20/15 and further aware that Mr. Patient was actively engaged in efforts to obtain renal transplant.

 

Dr. Physician suspected Herpes Zoster (shingles) and prescribed Valtrex (valacyclovir). According to the prescription authored by Dr. Physician and medication bottle provided by counsel, Mr. Patient was prescribed 3,000mg of Valtrex daily (1 G TID). Mr. Patient took his first dose on 11/20/15 and according to his wife’s testimony, took 3 total pills – one on 11/20 and two on 11/21. On 111/21, he did not feel up to driving himself to his morning dialysis session, unusual for him, and requested that his wife do so.  Upon discharge from dialysis, he was too weak to walk and required a wheelchair.

 

The following morning, Mr. Patient’s wife found him weak and incoherent on the family room floor with broken furniture surrounding him. She called an ambulance and Mr. Patient was taken to a hospital Emergency Department. He was admitted to the hospital not long after his presentation.

 

 

The following facts are relevant.

 

1.     Dr. Physician prescribed a full dose of Valtrex 3,000mg daily (1,000 mg TID); Valtrex is a pro-drug. It is converted to acyclovir in the body.

2.     Patient was admitted to the ED with an altered mental state (AMS)

3.     Patient’s medication history was noted to include a recent prescription for Valtrex (1,000 mg TID) and the altered mental and health state of the preceding day and morning were noted.

4.     A medical resident physician ordered 850mg IV acyclovir Q 8 H (2,550mg/day) at 18:17(pm). The order was discontinued at 19:15 (pm) after a hospital pharmacist’s intervention. The order was changed by another physician at 19:14 pm to a single dose of 850mg IV acyclovir to be given after dialysis, and confirmed / acknowledged by the hospital pharmacist at 19:18. This single 850mg dose, although subsequently a different dose was ordered (-500mg – see #6), was never discontinued; it was prepared and provided by the hospital pharmacy, and was administered at 619am 11/23/15, after hemodialysis was complete. The Medication Administration Record documents that this 850mg IV acyclovir dose was administered at 06:19 by a Nurse on the morning of 11/23/15. 

5.     At 20:15 pm on 11/22/15, a second medical resident issued a verbal order for acyclovir, which was re-calculated for ‘renal’ dosing  - 500 mg IV daily on dialysis days after dialysis. This was calculated according to the Renal Monitoring and Dosage Adjustment Policy, by the same hospital Pharmacist at 20:25pm on 11/22/15, and ordered to be given daily q 24h after dialysis. This 500mg IV acyclovir dose was administered to the Patient on 11/23/15 at 21:01 pm. This order is noted to be discontinued by another physician at 11:50pm on 11/25/15.

6.     On 11/23/15, the Patient received 850mg IV acyclovir at 0619 and 500mg at 21:01 = 1350mg total acyclovir within 15 hours of his last dialysis.

7.     All 1,350mg of IV acyclovir administered to Mr. Patient on 11/23 was verified and confirmed by the same hospital Pharmacist. 

8.     Valtrex toxicity was considered as the cause of the patient’s encephalopathy on 11/23/15.  Viral encephalitis was also considered in the differential.

9.     Acyclovir IV was continued until the end of November, with the exception of 11/26/15, when the dose was held for one day, and then restarted at 250mg/day.

10.  Valtrex encephalopathy was considered frequently as an alternative diagnosis to viral encephalitis until 11/26, at which time the Valtrex encephalopathy was confirmed.

11.  Mr. Patient’s mental state/encephalopathy improved when the acyclovir was discontinued.

 

 

 

OPINIONS

 

The expert held the following opinions with reasonable pharmacological and pharmaceutical certainty:

 

1. The appropriate renal dosing of oral Valacyclovir for an individual with no kidney function is 500mg per day.
2. The appropriate renal dosing of IV Acyclovir for an individual with no kidney function is 425mg per day.
3. No reason existed from a pharmaceutical standpoint to deviate from renal dosing protocols specific to Acyclovir. Moreover, the patient’s medical records do not evidence any physician requesting the pharmacy to deviate from renal dosing to orchestrate a deliberate plan of care. The depositions of Defendant physicians in the case reflect this as well.
4. The 1,000mg TID dose of Valtrex was an overdose in this anephric/dialysis patient.
5. The prescription for 1,000mg Valtrex caused severe neurotoxicity, encephalopathy, confusion, and physical impairments and necessitated his admission to the hospital Emergency Department.
6. The initial Emergency Department assessment of the patient noted the acute alteration of his mental state. His renal status (dialysis), his encephalopathy, and his Valtrex (valacyclovir) 3,000mg / day dose was noted.
7. The initial order for 850mg q 8 hours of intravenous acyclovir was a toxic/overdose and ignored the patient’s lack of renal function and dependence on dialysis and the need for a significantly reduced dose, recommended in the prescribing information (package insert) and the literature as 500mg/day.^{[1] [2]}  This was changed to a single dose, which still is a toxic overdose, and finally lowered to a 500mg dose. Even this reduction to 850mg/day dose calculation is double the dosing recommendation recommended in the AGH Renal Dosing Protocol (425mg) as well as in the FDA approved prescribing information. 
8. The 850mg acyclovir IV single dose was never discontinued by the Pharmacist. This being despite his involvement with consulting, verifying and confirmation of the subsequent 500mg ‘renal dose’. On its own, the 850mg dose is an overdose in a patient without kidney function. When combined with the 500mg dose 15 hours later and with no hemodialysis occurring in the interim, the overdose is multiplied and the effects exacerbated.
9. The Pharmacist, who provided the renal dosing consult, verified and modified the orders for IV acyclovir, and was ultimately responsible for approving the dispensing 1,350mg of IV Acyclovir to be administered the following day to a patient without kidney function, was negligent, and departed from the standard of care of a reasonable and prudent hospital pharmacist. The Pharmacist’s work and decision making also directly conflicted with the Hospital Renal Monitoring and Dosage Adjustment Policy. This negligence was a direct and proximate cause of the cardiac arrest the Patient suffered on 11/24/15.
10. The Patient received a second dose of acyclovir (500mg) on the second hospital day (11/23/15), essentially an overdose of the acyclovir, considering his renal failure. Hemodialysis can remove up to 33 - 60% of acyclovir.  This means that 30 - 60% of the remaining acyclovir from the 3,000 mg / day treatment of Valtrex remained after the dialysis.  Additional acyclovir, 850mg at 0619am and 500mg at 2100 were administered on 11/23, adding to the neurotoxicity of acyclovir.
11. The Patient’s encephalopathy improved after the acyclovir was discontinued.
12. The Patient’s morbidity and complications that developed after his admission were caused by the initial (Physician - Valtrex) and continued excessive and incorrect administration of acyclovir.  Had he been administered the correct renal dosing for Valtrex, he would not have become encephalopathic, which precipitated the ED admission.  Had the incorrect 850 mg IV acyclovir plus a second dose not been administered on 11/23, the Patient would have avoided the extreme acyclovir toxicity from which he suffered and further avoided the significantly increased risk of cardiac arrest that was ultimately realized.^[3]

 

 

DISCUSSION: BASES FOR OPINIONS

 

            REQUIREMENTS FOR DOSE ADJUSTMENT IN RENAL COMPROMISE OR FAILURE

 

            Major 

Valacyclovir (Includes valacyclovir) ↔ renal impairment^[4]

Severe Potential Hazard, High plausibility. Applies to: Renal Dysfunction

Valacyclovir is almost completely converted in vivo to acyclovir, which is primarily eliminated by the kidney. Patients with renal impairment may be at greater risk for neuro- and nephrotoxicity (including further deterioration in renal function, tubular damage and acute renal failure) from acyclovir due to decreased drug clearance. Therapy with valacyclovir should be administered cautiously in patients with renal impairment. Dosage adjustments are recommended in patients with moderate to severe renal dysfunction.

1.        "Product Information. Valtrex (valacyclovir)." Glaxo Wel

2.        lcome, Research Triangle Park, NC.

3.        Laskin OL, Longstreth JA, Whelton A, et al. "Acyclovir kinetics in end-stage renal disease." Clin Pharmacol Ther 31 (1982): 594-600

4.        Laskin OL, Longstreth JA, Whelton A, et al "Effect of renal failure on the pharmacokinetics of acyclovir." Am J Med 73 (1982): 197-201

PATIENTS WITH ACUTE OR CHRONIC RENAL IMPAIRMENT: Refer to DOSAGE AND ADMINISTRATION section for recommended doses, and adjust the dosing interval as indicated in Table 5.^[5]

Table 5 Dosage Adjustments for Patients with Renal Impairment
Creatinine Clearance (mL/min/1.73 m2)	Percent of Recommended Dose	Dosing Interval (hours)
> 50	100%	8
25 to 50	100%	12
10 to 25	100%	24
0 to 10	50%	24

Hemodialysis

In anuric(anephric) patients, acyclovir is slowly eliminated with a terminal plasma half-life of approximately 20 hours. The acyclovir total body clearance (29 ml/min/1.73m²) is only 10% of that seen in patients without renal impairment. Acyclovir is readily hemodialyzed with an extraction coefficient of 0.45. A single hemodialysis (6h) reduces acyclovir concentrations by up to 33^[6], 45 ^[7], or 60%.^[8]

 

 

NEED FOR PHARMACIST MONITORING

 

AGH recognized the need for dosage adjustment based upon compromised (or absent) renal function, as described in the AGH Renal Monitoring and Dosage Adjustment Policy.  Unfortunately, the Pharmacist in question did not discontinue the incorrectly calculated 850mg acyclovir dose.  Since the Acyclovir 850 mg IV single dose was not discontinued, it was treated as an active order, prepared by AGH pharmacy, delivered to the floor, and administered at 06:19(am) by a AGH nurse, according to the MAR.

 

 

All of the opinions expressed above were stated to a reasonable degree of pharmaceutical certainty and were based on the records received to date. The expert reserved the right to amend or supplement this report if additional information is made available.

 

 

Discussion Case B. CHALLENGING CAUSE OF DEATH IN A MALPRACTICE MATTER

 

FACTS OF THE CASE

 

On Thursday, November 29, 2007, Anthony Patient, a 42 year old, 110 pound, cerebral palsy, developmentally delayed male resident at a group home, was found unresponsive and shortly thereafter declared dead at the  Emergency Department, after unsuccessful resuscitation efforts  An autopsy and toxicology was performed, and a high level of sertraline, 2000mcg/L (200ug/L), was noted, with normal and untested (and therefore) no toxic levels for other medications being administered to Patient (lorazepam, olanzapine).  The autopsy (and therefore the toxicology specimens) was performed beginning at 1210pm on 12/30/07, ~36 hours after Tony Patient’s death.  A forensic pathologist ruled the causes of death as 1) Bronchopneumonia (principle), with 2) sertraline toxicity, and 3) partial bowel obstruction as contributing causes of death.  At autopsy, two plastic ‘stars’ were found embedded in the wall of his small intestine at the junction of the jejunum and ileum. The pathologist described necrotic tissue, a small fistula and partial bowel obstruction caused by these stars.

 

The patient started having respiratory complaints and signs and symptoms of acute respiratory disease in September, 2007, and was seen frequently (11 times) at a local urgent care center for his complaints. He was also treated for his respiratory complaints. (albuterol nebulizer / oral albuterol tablets, Z-Pak, prednisone, cephalexin, Mucinex)). His last visit was on November 28, 2007, the evening before he was found dead.   An X-ray demonstrated excess intestinal gas that was pushing up on his diaphragm.  The patient was last seen at 5am by the home staff, 90 to 120 minutes he was found unresponsive / in cardiac arrest. For several days before his death, the patient was experiencing diarrhea. There are no notations in the records that he was not eating and drinking, and the records indicate that sertraline (maximum dose – 200mg/day) and other medications were being administered.

 

The Coroner related that he inquired of a forensic toxicologist - Laboratory Director – who performed the post mortem toxicology, and the pathologist as to the cause of the excessive sertraline level.^[9] He was told that the sertraline tablets must have “accumulated at the site of the bowel obstruction and were released in one acute dose.”  Further, “the thought process in terms of why didn’t other medications accumulate – I believe that answer falls within the fact the other medications were given on a prn basis. But both the toxicologist and the pathologist stated that they truly could not explain why other medications didn’t do that, except for the fact that they were being given on a different dosing schedule.”  Later in the Inquest, the Coroner related that neither the pathologist nor the toxicologist would speculate on how much Sertraline the toxicology report concentration represented. “Neither physician felt comfortable coming up with a number that would actually be accurate.”

 

OPINIONS

 

The following opinions are expressed with reasonable pharmacological and pharmaceutical certainty.

 

1.  Zoloft / sertraline was probably not involved  or contributory to the death of the patient.
2. The patient was seen clinically the evening before – no signs of Serotonin Syndrome, which likely would be present if an overdose of sertraline was accumulating; the patient  was observed 2 hours before death was discovered. Onset could not be that fast – ie, 1.5 to 2 hours. Indeed, he may have died in the interim period between 5am and the time he was discovered in cardiac arrest.
3. The 2000 mcg/L sertraline level is probably inaccurate, an artificial elevation that occurs post-mortem (post-mortem distribution – PMD), as a result of the release of stored sertraline from muscles, liver, and other organs and tissues. While the PMD phenomenon is more pronounced in central (body) blood draws, it does occur in peripheral sampling, due to release from the large muscle masses in the femoral area of the lower extremity. contribution.
4. The pathologist and toxicologist both offered an explanation that “the Sertraline pills accumulated at the obstruction” and a toxic dose was released all at once”, but neither felt confident in that explanation, as the sertraline was the only toxic level found, and an obstruction would not select one tablet and allow others to pass. Neither was attempting to calculate the amount consumed – it could not be done.  Indeed, calculating pre-mortem levels from post-mortem concentrations is fraught with uncertainty.^[10]  
5. The patient had a partial obstruction.  Sertraline would disintegrate in the stomach and dissolution (change from tablet fragments to a liquid mixed with intestinal juices) would occur in the duodenum and jejunum, and substantial portions of sertraline doses administered would most likely be absorbed before the ‘obstruction’. This is a biopharmaceutical fact – this is how drug absorption works – tablets do not accumulate at a partial obstruction several feet into the small bowel.  Indeed, it was not a total obstruction – it was a partial obstruction. That means that medicine and foods would be digested in the bowel and pass through the obstruction.
6. The 2000mcg/L level of sertraline is not predictive for lethality ^[11]; survival has been reported at much higher levels (~ 2900mcg/L) in a patient who overdosed with 80 x 100mg tablets (8000mg)^[12]. Sertraline, and other drugs in its class, are surprisingly well tolerated, and considered much safer than earlier types of antidepressants.^[13]
7. A reasonable cause of death was present – bronchopneumonia, along with partial obstruction. Indeed, the intestinal gas inflating the loops of bowel and pressing up on the diaphragm would compromise the patient’s breathing, already compromised by his bronchopneumonia.
8. The medication count for Zoloft (sertraline) was accurate – no doses were missing or unaccounted for.  Doses are charted as being administered daily for the period before the patient’s death.
9. Several authoritative sources supported the expert’s opinions, as referenced.^[14]

 

SUMMARY AND CONCLUSION

 

Not surprisingly, the ‘lethal level of sertraline” peaked everyone’s interest. However, careful and informed analyses of this case caused the expert to conclude that this patient’s death was not caused or contributed to by sertraline. The ‘lethal’ sertraline level was most likely an artifact.  The clinical condition of the patient does not support sertraline toxicity on the day before his death.  The explanation of “all at once absorption” of a toxic dose is incompatible with known pharmaceutical sciences. Further, there was no missing sertraline to explain an accidental overdose of sertraline.

 

Discussion Case C. DETERMINATION OF THE EFFECTS OF MORPHINE IN A WILL CONTEST

 

              ASSIGNMENT

Evaluate, assess, and determine what effect(s) morphine administration had on the decedent during the period of October 1 – October 6, 2020.

 

FACTS OF THE CASE

The decedent died on October 6, 2020, two weeks after discharge (9/25/20) to Hospice care at home from a local hospital with a terminal diagnosis (widespread fallopian tube cancer). While hospitalized, she was started on morphine sublingual (2mg every (q) one hour) for analgesia purposes.

At home, morphine (liquid concentrate 20mg/ml) were ordered, both as a SCHEDULED dose, and a “PRN” – as needed:

-       2mg every 1 hours as needed for pain), and accelerating every few days.  

-       -September 28, 2020, the order was changed to Morphine 4mg q 4 hours SCHEDULED – PRN morphine 2mg/hour was also available.

-       September 29, 2020, the order was changed to Morphine 8mg q 4 hours (PRN dose also available)

-       October 2 or 3, 2020, a dosage increase for morphine (10mg q 4 hour SCHEDULED) was ordered On October 2, 2020, her morphine dose was 2mg q 1 hours as needed for pain.  For certain, the morphine dose was raised to 10mg q 4 hours the next day, October 3, 2020.

OPINIONS and BASES FOR OPINIONS

 

The expert’s opinions were expressed with reasonable pharmacological certainty.  

1. As a result of  cognitive impairing and disinhibiting effects of morphine on October 2, 2020, any decisions made by the decedent were subject to the influence of morphine.  Her ability to deliberate and consider the consequences of changing her estate plan on her death bed were suspect and fraught with risk.

 

Morphine, a strong opiate narcotic, disinhibits (releases) controls -  through a loss of inhibition. Morphine  is well-known to impair higher brain functions,^[15]  deliberation, memory, and cause clouding of the sensorium and judgment.^[16]  The patient need not ‘appear’ to be impaired. Executive functions, or the effects of impairment or inhibition, were not manifest in physical signs, levels of attention, communication, or responsiveness.

 

Drug-induced cognitive impairment is most commonly linked to opiates and some other Central Nervous System.^[17]  Opiates are known to cause confusion and a number of other adverse behavioral (cognitive) impairments/effects.^[18]  Both acute and chronic opioid use is associated with neuropsychological deficits in executive functions, attention, concentration, recall, visuospatial skills, and psychomotor speed.^[19]  Higher cortical executive functions are the first brain functions to be impaired; impairment of this level of brain functioning is not apparent to even a trained observer.  For reference (https://en.wikipedia.org/wiki/Executive_functions), basic cognitive processes refer to attentional control, cognitive inhibition, inhibitory control, working memory, and cognitive flexibility. Higher-order executive functions require the simultaneous use of multiple basic executive functions and include planning and fluid intelligence (e.g., reasoning and problem-solving).

Cells in the prefrontal cortex are involved in cognitive function.^[20] Brain frontal (cerebral) cortex  functions in value-guided decision-making. According to one view, each frontal cortical region is concerned with a different aspect of the process of learning about and evaluating choices and then selecting actions. An alternative view, however, sees sets of decision-making circuits working in parallel within the frontal lobes in order to make different types of decisions. While there is a neural circuit for making choices between pairs of simultaneously presented items in the manner that is frequently assessed in the laboratory, there is also evidence that other frontal lobe circuits have evolved to make other types of choices such as those made during the course of foraging.^[21] 

2. On October 2, morphine was prescribed at a SCHEDULED dose of 48-60mg/day, and a PRN dose of 48mg/day.

 

Discussion Case D. PROOF OF DRUG-INDUCED MENTAL CHANGES IN COMPLAINTANT IN SEXUAL ABUSE CASE

Ms. Complaintant, at age 17, accused Joseph Defendant, her former stepfather, of alleged sexaul abuse during the period when she was 5 or 6 until 12 years of age, during part of the period that Ms. Complaintant lived in the Defendant residence while Ms. Complaintant’s mother was married to the defendant. The Defendant vehemently denies any abuse, sexual or otherwise, occurred in the home or anywhere else.

 

Ms. Complaintant ‘told’ (led/prompted by) a school guidance/counselor of the alleged abuse in November, 2010, which precipitated a notification of child protective services, who notified the police. During the interview, because Ms. Complaintant was crying, the guidance counselor claims she could not speak so the guidance counselor asked her if her father (Defendant) abused her. Ms. Complaintant merely nodded in the affirmative. Thus, the guidance counselor put the allegations into the mouth of Ms. Complaintant while in an apparent vulnerable state. A police detective subsequently interviewed Ms. Complaintant; the police subsequently arranged for recording a telephone conversation between Ms. Complaintant and  Defendant, in which Ms. Complaintant repeatedly attempted to solicit discussions about and admissions to the sexual abuse. No admissions were made. Indeed, during the call, once Defendant realized and clarified Ms. Complaintant’s questions and statements, he was “shocked and numb”, in disbelief, that Ms. Complaintant would ever make those accusations.

 

Shortly after the recorded call between Ms. Complaintant and Defendant, the police interviewed the Defendant and arrested him.

 

Either before or or for 4 years since the time of the arrest, there have been no persons identified who witnessed any of the alleged abuse, and indeed, the alleged abuse was disclosed to the school Guidance Counselor in November 2010, more than 5 years after the last alleged abuse. Ms. Complaintant did not report any specifics, rather non-verbally (nodding) answered questions from the Guidance Counsellor suggesting certain behaviors/abuses. It has thus been approximately 9 years since the alleged abuse ceased. Ms. Complaintant, and 2 friends stated/testified that Ms. Complaintant instant messaged or texted (indirectly told them) that ‘something went on with her father’ – but no details were provided.

 

In the police interview, Ms. Complaintant was extremely vague about what happened, where it happened, how frequently it happened, ranging from a few times a week to as little as 10 or 12 total.

 

In a houseful of up to 10 people plus various Nannies and babysitters, no one in the family reported , witnessed, or was aware or even suspected any alleged sexual abuse by Mr. Defendant to Ms. Complaintant. Even complaintant’s mother stated “I never noticed anything unusual or suspected him - Defendant of any sexual behavior w/ Ms. Complaintant”

 

The arrest and the Indictment are based exclusively upon the allegations of abuse by Ms. Complaintant. The concept of CSAAS (Child Sexual Abuse Accommodation Syndrome) provides an explanation for delayed, accommodated, secretive, and/ or recantive statements regarding child sexual abuse, when the usual signs and symptoms of child sexual abuse are absent (discussed in detail later in this report). It has been introduced by an expert who has correctly identified CSAAS as a non-diagnostic report, only describing the phenomenon.

 

CSAAS, , is defined by an expert, who provides the caveat, “clearly it is not the purpose of this testimony to provide a diagnostic formulation or predictive statement in this matter.”  CSAAS, as defined, is offered only as an explanation for Ms. Complaintant’s repressed and delayed recitation of alleged repetitive sexual abuse by her step-father Defendant. CSAAS is considered controversial and is not accepted by all Courts and Jurisdictions as a basis for expert testimony.

Controversy exists over the reliability and scientific acceptance of CSAAS……Insofar that CSAAS is one explanation, , there are others:^[22]

ASSIGNMENT

The expert has been asked by Mr. Defendant’s attorneys to review this matter and, if able, provide expert opinion related to any toxic and psychiatric effects Accutane had on Ms. Complaintant, and if, in the expert’s opinion, the Accutane adversely affected her memory and psyche, leading to false allegations of sexual abuse by Defendant.

 Therefore, the expert discussed the psychiatric toxicity effects on Ms. Complaintant during and following the period of her treatment with Accutane (isotretinoin), a drug prescribed for cystic acne. 

The expert notes that no mental, psychological, or psychiatric experts have opined that Ms. Complaintant was sexually abused.

The expert requested permission to interview Ms. Complaintant, but she has declined the invitation (letter of the Prosecutor).

It appears that the CSAAS theory is offered when the usual presentation of child sexual abuse is not manifest.

FACTS OF THE CASE RELEVANT TO ASSESSMENT AND OPINIONS

1. Accutane is considered a drug with significant and substantial psychiatric toxicities, including depression, psychosis^[23], suicidality, delusions, and nightmares. The US FDA Medwatch analysis for Accutane / Isotretinoin documents the drug’s psychiatric toxicity; so do the published scientific literature, as well as books and published articles by the consulting expert in the field document the Accutane psychiatric toxicity.
2. Ms. Complaintant did not begin to experience or be observed to have any behavior changes through her early years until after the Accutane was prescribed and consumed for a period of 6 to 7 months during the 3^rd and 4^th Quarter of 2008 .
3. Ms. Complaintant’s accusations followed a period of significant Accutane toxicity (dermatology records, investigation of Accutane Class action lawsuit). Ms. Complaintant testified that she became depressed and wanted to take her own life.
4. Ms. Complaintant and her friends and family have stated/testified that she was not depressed and withdrawn through her early years until she was exposed to Accutane. (Transcript of Hearing, June 25, 2014; Testimony of Ms. Complaintant ), Transcript of Pre-Trial Hearing, April 24, 2013;. “Having lived with (the complaintant), I saw the changes in her when she was taking Accutane and I know that these ‘allegations’ came completely out of the blue once she was experiencing the side effects of Accutane” (Certification of a brother of Defendant).
5. Even after the accusation of the alleged sexual abuse, Ms. Complaintant behaved erratically and ambiguously toward Mr. Defendant. For example, she acted positively toward Mr. Defendant after her separation from his household, went to his house, interacted on the sports fields, hugged him publicly, etc. Even after his arrest, she visited his next door neighbor several times where she could run into him, including overnight visits and sunning herself on their deck which his kitchen window and deck overlooked. Excerpts from the Accutane Psychiatric toxicity chapter from one of the expert’s books^[24]

 

ACCUTANE

Psychiatric toxicities experienced with Accutane (isotretinoin), as described by the manufacturer, include irritability, feeling unusually tired, changes in normal sleep patterns, and difficulty breathing or wheezing. Post-marketing reports show that major depression, psychosis, and rarely, suicidal ideation, suicide attempts and suicide may be caused by Accutane. Moreover, these conditions can continue after the Accutane is discontinued.

Accutane has had a very rocky clinical development and regulatory history. Roche developed Accutane in 1971 and in 1982 Roche filed a New Drug Application, which was approved for the treatment of severe cystic acne which is unresponsive to other treatments. Shortly after marketing, FDA and Roche received reports of Accutane-related birth defects, and warnings of increasing strength were put in the prescribing information.

 

Neuropsychiatric Adverse Effects of Accutane

The 1983 AE Report published that 5.5% (6/110) of patients with acne experienced depressive symptoms, manifested by malaise, crying spells and forgetfulness, within 2 weeks of commencing isotretinoin therapy ^[25].

Roche amended Accutane's prescribing information in 1985 under 'Adverse Reactions' to state: "The following CNS reactions have been reported and may bear no relationship to therapy - seizures, emotional. Again, in 1986, Roche amended Accutane's prescribing information to state: "Depression has been reported in some patients on Accutane therapy. In some of these patients, this has subsided with discontinuation and recurred with reinstitution of therapy.”

 

A case report (1989) discussed a patient who reported the onset of hallucinations and paranoia on day 11 of isotretinoin therapy, which subsided when drug intake was stopped and recurred shortly after resumption of isotretinoin.^[26]. Scheinman et al (1990) reported that 1% of patients treated developed depressive symptoms with oral isotretinoin*, which were diagnosed by a psychiatrist, and the severity of symptoms interfered with their normal functioning. The relationship of depression to isotretinoin therapy was confirmed by rechallenge.^[27]

 

The FDA initiated discussions with Roche (May 1997) concerning reports of serious psychiatric disorders associated with Accutane. At that time, the FDA apparently was unaware of a new French warning.

 

On November 24, 1997, Roche received a letter from the Department of Health & Human Services, requesting the following change in the labeling be incorporated to furnish adequate information for the safe and effective use of Accutane.

●        Psychiatric Disorder: Accutane has been associated with a number of cases of severe depression, psychosis, suicide attempts, and suicide. Follow-up visits during Accutane treatment should include specific questioning regarding psychiatric signs and symptoms. Patients should be specifically warned to immediately discontinue Accutane use and seek medical evaluation if depression or mood changes occur. These adverse reactions have been reported for patients with and without previous psychiatric symptoms. It is not known whether a history of psychiatric disorder or pre-existing depression increases the risk associated with Accutane. In some of the reported cases, depression has resolved with discontinuation of Accutane and reoccurred with the reinstitution of therapy.

 

"ADVERSE REACTIONS - In the post-marketing period, a number of patients treated with Accutane have reported depression, psychosis and rarely, suicidal, ideation, suicide attempts and suicide. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy."

 

May 1, 2000: Roche changed the warnings on the prescribing information to include: "...DEPRESSION, AND RARELY SUICIDAL THOUGHTS, SUICIDE ATTEMPTS AND SUICIDE..." This is the first time that the actual packaging contains the full psychiatric warnings.

Accutane serious adverse events (1998-2000) were reviewed August 3, 2000. Statistics were derived from the FDA’s Adverse Event Reporting System (AERS).

2000 – 7 suicides; 1999 – 15 suicides; 1998 – 32 suicides.

 

The January 2001 Medication Guide for Accutane noted:

●        #2 Mental problems and suicide. Some patients, while taking Accutane or soon after stopping Accutane, have become depressed or developed serious mental problems. Signs of these problems include feelings of sadness, irritability, unusual tiredness, trouble concentrating, and loss of appetite. Some patients taking Accutane have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. No one knows if Accutane caused these behaviors or if they would have happened even if the person did not take Accutane.

 

CAUSATION ANALYSIS

 

Comments on the Individual Riddell Criteria for Establishing Causation in the Accutane Case under discussion

1. Temporal Eligibility: Ms. Complaintant had no psychiatric toxicity before Accutane; Accutane toxicity does not always diminish with the cessation of the drug.)
2. Latent Period:: Ms. Complaintant developed toxicity while taking Accutane and which continued after the Accutane was discontinued).
3. Exclusion: It is important to rule out the effect of concurrent medications or underlying medical conditions as alternative hypotheses. (Comment: Ms. Complaintant developed psychiatric toxicity after starting Accutane. No other possible causes were known. Accutane was known to cause psychiatric toxicity. The accusations of alleged sexual abuse surfaced in the form of a fresh complaint, whose validity the defense disputes, 6 months after the Accutane was discontinued, according to a date determined by the court in deciding the admissibility of the fresh complaint. This alleged fresh complaint occurred during and after the behaviors associated with the psychological and psychiatric toxicities attributable to Accutane were occurring).

 

4. De-challenge: The disappearance or improvement of an adverse event after the withdrawal of the treatment is a positive indication of relatedness. Adverse events can however persist after the treatment is withdrawn, which indicates either that there was no relatedness, or that the adverse effect is a persistent injury. (Comment: psychiatric toxicities are often persistent, frequently lasting long after the intoxicating agent is removed).

 

5. Re-challenge: Re-Introduction of a treatment which is associated with the same or similar adverse event is a good indication of causation. If the adverse event does not reappear, this can be a sign of lack of causation, but may also indicate the development of tolerance. Of course, since the potential association in the first place may prevent the reintroduction of the suspect treatment (re-administration of penicillin to a person with an allergic history to penicillin), re-challenge is not intentionally done.

 

6. Singularity of the drug: It is important to determine whether there is something unique about the adverse reaction experience that is not consistent with any other drug taken or any existing disease condition. There is no evidence that Ms. Complaintant took any other drugs that could have caused these psychological or psychiatric behaviors. There is overwhelming evidence that Accutane causes psychiatric toxicity, and a close chemical -  high dose Vitamin A, is also known to cause similar brain and psychiatric toxicities.^{[28] [29]}

 

7. Pattern:  It is important to determine whether similar adverse effects have been described in the literature with the treatment in question or another in the same therapeutic class, or it may refer to a morphologic pattern in a target organ that suggests an association with a particular drug or group of drugs.
8. Drug Identification:  (Comment: There is no question of drug identification in this case. Ms. Complaintant acknowledges that she took Accutane. The Pharmacy records clearly note the dispensing of Accutane. And Ms. Complaintant inquired into participating in a Class Action lawsuit for injuries caused by Accutane.).

 

OPINIONS

The following expert opinions were expressed with reasonable pharmacological certainty.

1. The facts and determinants in this matter meet the requirements of a causation determination between Accutane and psychiatric toxicity in Ms. Complaintant;

 

2. Ms. Complaintant does not present with the usual pattern of a sexually abused child (thus the introduction / suggestion of CSAAS); Behaviors reported in a child that suggests sexual abuse includes nighmares or other sleep problems without an explanation, seems distracted or distant at odd times, has a sudden change in eating habits (refuses to eat, loses or drastically increases appetite, has trouble swallowing), sudden mood swings – rage, fear, insecurity or withdrawal, leaves clues that seem likely to provoke a discussion about sexual issues, writes, draws, plays or dreams of sexual or frightening images, develops new or unusual fear of certain people or places, talks about a new older friend, suddenly has money, toys or other gifts without reason, thinks of self or body as repulsive, dirty or bad, exhibits adult-like sexual behaviours, language and knowledge, has new words for private body parts, resists removing clothes when appropriate (bath, bed, toileting, diapering), asks other children to behave sexually or play sexual games, mimics adult-like sexual behaviors with toys or stuffed animals, wetting and soiling accidents unrelated to toilet training). ^[30] Indeed, Ms. Complaintant’s pattern of behavior differs from that of a sexually abused child, e.g., visiting the next door neighbor, writing a letter stating she wanted to keep seeing him, hugging and kissing him on the sports field after making allegations against him, (Certification of Joseph Defendant), continuing to come over to the Defendant Residence after she, her mother, and brother moved out in July, 2008 (Certification of Cody Defendant, Certification of Michael Defendant)..

 

3. Ms. Complaintant’s reports of (and observations of her being) depressed and ‘dreams and memories’, and allegations of sexual abuse are probably (more likely than not) caused by her exposure to Accutane, suffering significant toxicity to Accutane, including psychiatric toxicity, ‘schizophrenic-like’ actions, and psychosis – a ‘loss of contact with reality’^[31]. The fact that her mother was separated from and being divorced by Mr. Defendant can exacerbate any psychological or psychiatric toxicity (such as the Accutane toxicity). Additionally, she exhibited moodiness, irritability, crying spells, staring episodes, inconsistent attitudes regarding wanting to socialize and interact with Mr. Defendant and her stepbrothers, and other personality disorders as set forth by the father and a brother.
4. Ms. Complaintant’s dreams and memories began after she experienced significant toxicity to Accutane. Distortion of dreams and thoughts are manifestations of drug-related dreams; stress (divorce) increases the vulnerability to and likelihood of psychiatric effects, including agitation, delusions, and depression.
   
   
5. Ms. Complaintant’s attribution of guilt to Defendant is probably distorted by her Accutane psychiatric toxicity. (See #4)

 

6. The temporal relationship (exposure before disclosure) of Accutane is a more likely cause of her depression and mental changes than CSAAS behaviors. Accutane is well-known to cause significant psychiatric toxicity.

 

7. Ms. Complaintant does not fit the profile of someone who was sexually abused and, in fact, appears to not have been sexually abused;

 

This case went to a criminal trial. The author of this causation report (James T. O’Donnell) testified on behalf of the Defendant.  The Jury acquitted the Defendant of all charges against him.

 

Several other chapters in this book contain causation opinions that apply these criteria in the factual settings of the cases.

 

15.12 Summary

 

The determination of causation of an adverse effect by a medical treatment is complex. Only by applying a structured, scientific approach consistent with established criteria can an accurate causal assessment be reached.

 

Endnotes

 

1.   “Title 21: Food and Drugs; Part 310.305(b): New Drugs; Records and Reports; Definitions.” Code of Federal Regulations. Washington DC: U.S. Government Printing Office.

 

2.   Camilleri, M. “Safety concerns about alosetron.” Arch Intern Med. 2002 Jan 14;162(1):100-101.

 

3.   Karch FE, Lasagna L. Towards the operational identification of adverse drug reactions. Clin Pharmacol Ther. 1977 Mar;21(3):247-54.

 

4.   Marks DH. Depression Leading to Suicide As An Adverse Effect of Metoclopramide. www.ispub.com/ostia/index.php?xmlFilePath=journals/ijge/vol5n2/depression.xml. Internet Journal of Gastroenterology [peer-reviewed serial on the Internet]. 2007. Volume 5(2).

5. Ma P, Marinovic I, Karaca-Mandic P. Drug Manufacturers’ Delayed Disclosure of Serious and Unexpected Adverse Events to the US Food and Drug Administration. JAMA Intern Med. Published online July 27, 2015. doi:10.1001/jamainternmed.2015.3565.

 

 

 

6.   Hutchinson TA, Lane DA. Assessing methods for causality assessment. J Clin Epidemiol 1989, 42: 5-16.

7. Koch Robert (1893). “Über den augenblicklichen Stand der bakteriologischen Choleradiagnose” (in German). Zeitschrift für Hygiene und Infectionskrankheiten 14: 319–333; Koch Robert (1884). “2 Die Aetiologie der Tuberkulose”. Mitt Kaiser Gesundh. pp. 1–88.

 

 

8.   Doll R. Sir Austin Bradford Hill and the progress of medical science. BMJ. 1992 Dec 19; 305(6868): 1521–1526.

 

9.   Morabia A. On the origin of Hill’s causal criteria. Epidemiology. 1991 Sep;2(5):367-9.

 

10. Riddell RH., ed. Pathology of Drug-Induced and Toxic Diseases. Churchill Livingstone, New York, 1982 (3-9).

 

11.       Horwitz RI, Feinstein AR, Harvey MR. Temporal Precedence and other problems of the exposure-disease relationship. Arch Intern Med. 1984 Jun;144(6):1257-1259.

 

12. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV. “Valvular heart disease associated with fenfluramine–phentermine.” N Engl J Med. 1997 Aug 28;337(9):581-588.

 

13. Jick H, Vessey MP. Case-control studies in the evaluation of drug-induced illness. Am J Epidemiol. 1978 Jan;107(1):1-7.

 

14. Jones JK. Determining Causation from Case Reports, in Strom BL, Pharmacoepidemiology, Second Edition, Wiley, New York, 1994

 

15. Austin H, Hill HA, Flanders D, Greenberg RS. Limitations in the applications of case-control methodology. Epidemiol Rev. 1994;16(1):65-76.

 

16. Breslow NE, Day NE. Statistical Methods in Cancer Research. Volume I -The Analysis of Case-Control Studies Lyon: International Agency for Research on Cancer; 1980.

 

17. Schlesselman JJ. Case-Control Studies. Design, Conduct, Analysis New York: Oxford University Press; 1982.

 

18. Kazdin A. Single-Case Research Designs. New York: Oxford University Press; 1982.

19. . Yun H, Curtis JR. New methods for determining comparative effectiveness in rheumatoid arthritis. Curr Opin Rheumatol. 2013 May;25(3):325-33. 

 

 

20. Hill AB. The environment and disease: association or causation. Proc R Soc Med. 1965 May; 58(5): 295–300.

 

21. Girard M. Conclusiveness of rechallenge in the interpretation of adverse drug reactions. Br J Clin Pharmacol. 1987 Jan;23(1):73-79.

 

22. Stevens M. Deliberate drug rechallenge. Hum Toxicol. 1983 Oct;2(4):573-577.

 

23. Causality assessment of adverse events following immunization. Weekly Epidemiology Record. WHO. 23 March 2001:

 

 

24. Marks DH. Neurologic Complications of Vaccination with Outer Surface Protein A (OspA). The International Journal of Risk and Safety in Medicine, 2011 Jan 1;23(2):89-96.

 

 

25. Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579, 113 S.Ct. 2786, 125 L.Ed.2d 469 (1993).

 

26. Daubert v Merrill Dow Pharmaceuticals, Inc., 43 F.3d 1311, 1317 (9th Cir. 1995)

27.Reference Manual On Scientific Evidence, 2nd ed., Federal Judicial Center, 2000

 

28. Sackett DL. Bias in analytic research. Journal of Chronic Diseases. 1979;32:51-63.

 

29 Thames LD and Martin L. The Pharmacologist as an Expert Witness. In-House Defense Quarterly.Winter, 28 – 31. 2009. Defense Research Institute. Chicago.

 

30. www.abcp.net

 

31. Agee, 2004 WL 5352989 at *2, McClain, 401 F.3d at 1240-44, Tidwell, 626 So. 2d at 1300, Ashman . SK&F Lab Co., 702 F.Supp. at 1405, Crisostomo 857 F.2d at 1153, Hermes 848F.2d at 69, Holley 348 S.E.3d at 776-77).

 

32 AAFP . Physician expert witness in medical liability suits.  http://www.aafp.org/about/policies/all/physician-expert.html

 

33 AMA Opinion 9.07 - Medical Testimony, December 2004.

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