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McCarrell v. Hoffman-LA Roche

March 12, 2009

ANDREW MCCARRELL, PLAINTIFF-RESPONDENT,
v.
HOFFMAN-LA ROCHE, INC., AND ROCHE LABORATORIES, INC., DEFENDANTS-APPELLANTS.



On appeal from the Superior Court of New Jersey, Law Division, Atlantic County, Docket No. L-1951-03.

Per curiam.

NOT FOR PUBLICATION WITHOUT THE APPROVAL OF THE APPELLATE DIVISION

Argued December 1, 2008

Before Judges R. B. Coleman, Sabatino and Simonelli.

This appeal arises out of a lawsuit filed by plaintiff Andrew McCarrell, a resident of Alabama, against defendants Hoffman-LaRoche and Roche Laboratories (collectively, "Roche"), which manufactured and distributed the prescription drug Accutane. Plaintiff alleged that as a result of taking Accutane for an acne condition, he developed inflammatory bowel disease ("IBD"). The IBD led to the surgical removal of his colon and other serious medical complications. A jury returned a verdict in plaintiff's favor on his products liability claim against Roche, but not on his consumer fraud claim, and awarded him compensatory damages.

On appeal, Roche challenges several rulings by the trial court, including the court's admission of the testimony of plaintiff's causation expert; the admission and use of various internal Roche documents, including records known as causality assessments; the exclusion of certain defense proofs relating to the number of Accutane users; and the denial of Roche's motions for judgment on various grounds.

We affirm the trial court's admission of testimony from plaintiff's causation expert. We also affirm the trial court's other rulings appealed by Roche, with a significant exception. Specifically, we hold that the court's restrictions upon the defense presenting to the jury certain background evidence about the number of Accutane users constituted reversible and harmful error. Consequently, the judgment must be vacated, and the matter remanded for a new trial. On remand, the trial court shall also consider Roche's contention that plaintiff's failure-to-warn claims are preempted by federal law, in light of the United States Supreme Court's recent opinion in Wyeth v. Levine, 555 U.S. ___, ___ S.Ct. ____, ____ L.Ed. 2d ____, No. 06-1249 (March 4, 2009).

I.

We shall not attempt to state comprehensively the proofs that emerged in the extensive pretrial proceedings and at the lengthy jury trial that consumed fifteen days. We instead summarize the facts most significant to the issues Roche has raised on appeal.

A. Accutane

Accutane is a prescription medication developed by Roche. It was approved by the Food and Drug Administration ("FDA") in 1982 to treat recalcitrant nodular acne, a severe and disfiguring skin disease characterized by large, inflamed cystic lesions on the patient's face and back.

Chemically, Accutane is isotretinoin, or 13-cis-retinoic acid. It is part of the family of drugs known as retinoids, vitamin A derivatives. Roche initially studied the use of retinoids as potential chemotherapy for the treatment of cancer. As a result of its research, Roche discovered that retinoids were effective in treating nodular acne.

Although the exact "mechanism of action" for how Accutane works is unknown, Roche discovered that the drug was effective in suppressing the production of oil and waxy material produced in the sebaceous glands. Nodular acne is caused by the accumulation of sebum under the skin, which ultimately ruptures the follicle wall, forming an inflamed nodule. Accutane was found to be highly effective in treating nodular acne that has been recalcitrant to standard treatments.

Accutane is a teratogen, meaning that there is a high risk that if a woman takes the drug while pregnant, her child will be born with life-threatening birth defects. Additionally, common adverse effects from Accutane include dry skin, lips, and eyes, conjunctivitis, decreased night vision, muscle and joint aches, and elevated triglycerides.

Prior to receiving FDA approval for Accutane, Roche conducted several pre-clinical studies of the drug, using dogs. Those studies revealed instances of gastrointestinal bleeding in the treated dogs.*fn1

Roche also conducted a pre-FDA approval clinical study of Accutane on 523 patients, 21.6% of whom suffered some gastrointestinal side effects. Nevertheless, Roche did not include any warnings about IBD on the original 1982 Accutane label.

B. IBD

IBD is a chronic idiopathic inflammation of the small bowel and the colon. IBD most commonly presents as one of two diseases: Crohn's disease or ulcerative colitis. Ulcerative colitis is a chronic inflammation and ulceration of the inner lining of the cells of the colon. Crohn's disease is similar to ulcerative colitis, in that it causes inflammation and ulcers, but it can attack any part of the digestive tract from the mouth to the anus. Patients with Crohn's disease commonly experience abscesses, fistulae, and fissures within the bowel and around the rectum and anus. IBD occurs when a trigger sets off an immune reaction, or inflammation, and for some reason the patient is unable to regulate the body's response.

The causes of IBD remain largely unknown. However, several factors are associated with a statistically-increased rate of IBD, including family history, prior infections, and the frequent use of antibiotics. The peak age of onset of IBD is young adulthood.

IBD is a permanent condition, although the symptoms may remit and recur. The common symptoms of IBD include diarrhea, gastrointestinal bleeding and rectal bleeding. About seventy percent of patients diagnosed with Crohn's disease undergo surgery to remove their colon.

C. Roche's Warnings About Accutane

After it began selling Accutane, Roche received several post-marketing reports of patients who had developed IBD following their use of the drug. By 1983 Roche had received "more than a handful" of reports of IBD and peptic ulceration in Accutane users, particularly in patients taking the drug outside of the clinical trial. Dr. William Cunningham, director of medical affairs for Roche, testified that he could not then determine what the relationship was, because we only had a handful [of reports]. . . . [B]y this time [i.e., 1983] . . . we estimated about 300,000 patients had been treated . . . so we had about six or seven or eight patients with these two diseases in a total population of about 300,000.

Roche did not perform clinical trials to test the relationship between Accutane and IBD. Nonetheless, it made certain labeling changes after it received this additional risk information in the early 1980s.

Specifically, in March 1984, Roche revised the Accutane warning, explaining in a "Dear Doctor" letter that:

Ten Accutane patients have experienced gastrointestinal disorders characteristic of inflammatory bowel disease (including 4 ileitis [inflammation of the small intestine] and 6 colitis [inflammation of the colon, a form of ulcerative colitis]). While these disorders have been temporally associated with Accutane administration, i.e., they occurred while the patients were using the drug, a precise cause and effect relationship has not been shown. Roche is continuing to monitor adverse experiences in an effort to determine the relationship between Accutane . . . and these disorders. [(Emphasis added).]

Roche also amended the "WARNINGS" section of the Accutane label (or package insert provided to physicians) to include the following:

Inflammatory Bowel Disease: Accutane has been temporally associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Accutane immediately.*fn2

[(Emphasis added).]

Dr. Cunningham was involved in developing Accutane and in designing the product's label. He explained that the term "temporal," (or "temporally") as used in the "Dear Doctor" letter, meant "somehow relating to the time, implying the time of administration [of the drug]."

Nurse Eileen Leach, medical director of dermatology at Roche, offered similar testimony. She contended that the term "temporal," as used in this context, meant that "during the time that the patient was taking Accutane, they developed symptoms, or they reported symptoms." She elaborated that the word "associated" meant that Roche had received reports of an adverse event. According to Leach, such language contrasts with the term "cause," which would connote a biological connection between the adverse event and the use of the drug.

Roche's Sales Desk Reference, a manual used by the company's sales personnel in answering questions about its drug products, stated that some Accutane patients had experienced symptoms characteristic of IBD. The manual added that "[t]hese disorders have been temporally associated with Accutane administration, that is to say, the symptoms occurred while the patients were receiving the drug."

Dr. Martin Huber, head of drug safety for Roche, differed with the definition of "temporally" contained in the sales manual. He claimed the term meant that "it occurs in a reasonable temporal association," or within a reasonable time after taking the drug. Dr. Huber acknowledged that if Accutane caused IBD, the symptoms might not become readily apparent until after a patient had stopped taking the drug.

Roche also published a patient brochure for Accutane. The brochure contained a warning about the drug's possible gastrointestinal side effects. The brochure stated, in pertinent part, that "ACCUTANE MAY CAUSE SOME LESS COMMON, BUT MORE SERIOUS SIDE EFFECTS" and patients should be "ALERT" for "SEVERE STOMACH PAIN, DIARRHEA, RECTAL BLEEDING." Patients were advised in the brochure that if they "EXPERIENCE ANY OF THESE SYMPTOMS" they should discontinue taking Accutane and check with their doctor.

Patients were further warned in the brochure that these symptoms "MAY BE THE EARLY SIGNS OF MORE SERIOUS SIDE EFFECTS WHICH, IF LEFT UNTREATED, COULD POSSIBLY RESULT IN PERMANENT EFFECTS." The same warnings were reprinted on the blister packaging for Accutane. These warnings remained unchanged as of 1995, when plaintiff began using the drug.

D. Post-Marketing Monitoring and Causality Assessments

After Accutane was approved for sale, Roche was obligated to monitor the safety of the drug on a continual basis and to report safety findings to the FDA. Dr. Alan Bess, then head of drug safety for Roche in the United States, was responsible for collecting the data on adverse drug reaction ("ADR") reports the company received about Accutane. As Dr. Bess indicated, Roche received such reports through its call center. The calls came from physicians, pharmacists, patients, family members, and attorneys. Roche also received information indirectly through MedWatch, the FDA's voluntary reporting program.

Various Roche employees, generally nurses and drug safety associates, responded to adverse event reports that came into the call center. These employees recorded each caller's responses on the MedWatch form. That form included entries for the duration of the Accutane therapy, the drug dosage, the age and sex of the patient, his or her family and medical history, the onset of symptoms, the ultimate outcome, and whether the adverse event abated after the patient stopped using the drug. A Roche medical reviewer typically examined each ADR report and contacted the patient, doctor, or reporter to obtain missing information, including copies of the patient's medical reports.

Dr. Bess explained that the goal of this ADR review process was to obtain as much accurate information as possible to enable Roche to "make a determination as to whether the drug was in any way responsible for causing" the adverse event. Dr. Bess described the process as a "pretty vigilant system," and said his group was often successful in getting all of the necessary information.

Roche logged the information from the ADR reports into a database known as "ADVENT." If the reporter of an ADR provided the company with his or her assessment of an alleged relationship between Accutane and the adverse effect, Roche would record that assessment. Roche would do so by noting the reporter's assessment in the ADVENT data field.

The ADVENT database also contained a specific field that reflected the company's own assessment of potential relatedness of the adverse event to the drug. A "yes" response in this data field could signify that the company had found a reasonable probability that the adverse event is related to the drug. In that regard, Roche reviewed the individual reports of adverse events, obtained additional information when necessary, and made its own assessments of causality. The ADVENT database also contained a Council for International Organizations of Medical Sciences ("CIOMS") field, in which Roche supplied a narrative discussion of the potential causal relationship between the adverse event and the drug treatment.

Dr. Huber explained that such so-called "causality assessments" are performed by Roche to identify cases that warrant a more thorough evaluation. They are required by regulation to be conducted in Europe, but not in the United States. He testified that, despite the nomenclature, "causality" assessments are not conducted to determine actual causality, but rather to determine whether there is simply evidence of an "association" between the adverse effect and use of the drug. He contended that the causality assessments help Roche personnel understand if "we see enough evidence that we need to take action."

Dr. Bess, on the other hand, defined a causality assessment differently than Dr. Huber. Dr. Bess described the term as one "used in the world of drug safety to demonstrate a relationship, a cause and effect relationship, between the drug and an adverse event."

In assessing causality, Roche utilized the "Naranjo algorithm," a questionnaire created to help determine the likelihood of whether an adverse drug reaction is related to the drug's use.*fn3 The Naranjo algorithm was scientifically designed to decrease, in particular, inter-observer variability. It consists of ten "yes" or "no" questions, expressed as follows:

QuestionYesNoDo Not KnowScore 1. Are there previous conclusive reports on this reaction?  2. Did the adverse event appear after the suspected drug was administered?-1  3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?  4. Did the adverse reactions appear when the drug was readministered?-1  5. Are there alternative causes (other than the drug) that could on their own have caused the reaction?-1  6. Did the reaction reappear when a placebo was given?-1_1  7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?  8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?  9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?  10. Was the adverse event confirmed by any objective evidence? 

Points are added or subtracted to the Naranjo algorithm based on the answer to each of the questions, generating a total score ranging from -2 to . The total score classifies each particular case as either "highly probable" (>8 points), "probable" (5-8 points), "possible" (1-4 points), or "doubtful" (0 points).*fn4

Health care professionals at Roche used this Naranjo scoring method to conduct the primary review of the reported ADR information. The results were then sent to Roche's headquarters in Switzerland, where, according to Dr. Huber, a physician would review the results to "see if there was anything they felt from a medical point of view needed to be adjusted."

Dr. Daniel Reshef, a physician and director of drug safety at Roche, conducted a final review of the Accutane causality assessments. Dr. Reshef made his own independent medical judgment as to whether they were correct. The reviewed assessments were included in the ADVENT database, but Roche was not required to submit them to the FDA.

Periodically, Roche, like other pharmaceutical companies, prepared internal reports evaluating the ADR reports. In one such document, entitled "Internal Causality Assessment," Roche stated that through January 6, 1994, 104 colitis and related syndromes, including Crohn's disease, had been reported in Accutane users. Of those 104 cases, 33 were given a "possible" or "probable" causality rating. Based on that information, Dr. H. Lefrancq,*fn5 a physician with Roche, commented in a February 24, 1994 internal memorandum that "[i]t is reasonable to conclude from this data, that in rare cases Roaccutane [Accutane's brand name in Europe] may induce or aggravate a pre-existing colitis."

Dr. Peter Schifferdecker, also a physician employed by Roche, reviewed the post-marketing ADR reports received from patients using Roaccutane for the six-month period from January 1 through June 30, 1988. In his internal report dated August 17, 1988, Dr. Schifferdecker wrote that "[s]ince [the drug's] introduction, Roche Drug Safety received 38 case reports of colitis and proctitis in association with Roaccutane treatment." He added that "[a] history of diarrhea, or colitis, or rectal bleeding was reported in six patients, suggesting a pre-existing irritability of the intestinal mucosa in these patients with a possible exacerbation or aggravation of these symptoms by Roaccutane." Dr. Schifferdecker concluded:

It appears that cases of colitis and proctitis reported to Roche . . . are within the spontaneous incidence rates of the background population, although underreporting of such cases may occur. It should be stressed that approximately one half of the patients were at a certain risk for the development of colitis prior to Roaccutane treatment. Although there is evidence from in vitro and animal experiments that Roaccutane may protect the organism from experimental colitis, Roche . . . will further monitor closely cases of colitis and proctitis reported in association with Roaccutane treatment. [(Emphasis added).]

Despite this recognition by Dr. Schifferdecker in 1988 of the need for close monitoring, Roche did not thereafter conduct any clinical trials or epidemiological studies as to whether Accutane caused IBD.

E. Plaintiff's Use of Accutane and His Injuries

On March 6, 1995, plaintiff, who was then twenty-three years old, saw Dr. Ann Gerald, an Alabama dermatologist, for treatment of acne. Dr. Gerald's records indicate her perception at the time that plaintiff had "been treated for the past 5 or 6 years with antibiotics" and that he was "getting afraid" to continue taking them. However, plaintiff testified that he told Dr. Gerald that he had taken antibiotics "five or six years ago," not that he had been on a continuous course of antibiotics.

It is undisputed that during her initial consultation with plaintiff, Dr. Gerald discussed Accutane and certain of its side effects with him. Dr. Gerald stated it was her practice to discuss with her patients only Accutane's common side effects, which included teratogenicity, elevated triglycerides and lipids, dry eyes, dry skin, chapped lips, vision problems, and headaches.

The information provided in the Accutane label about IBD did not indicate to Dr. Gerald that IBD was a significant risk for plaintiff because he did not have a family history of bowel disorders. Moreover, she understood the phrase "temporally associated," as used in the "Dear Doctor" letter, to mean that the identified side effects would appear only at the time of Accutane's administration to the patient and not after the drug had been discontinued.

Dr. Gerald also typically gave her patients the Accutane patient brochure. As we have already noted, the brochure contained the warning that Accutane may cause less common, but more serious, side effects, such as severe stomach pain, diarrhea, and rectal bleeding. Dr. Gerald admitted, however, that there was no indication in her file, as she claimed was her practice, that she had specifically given plaintiff the brochure.

Plaintiff insisted that Dr. Gerald never warned him that Accutane could cause permanent IBD. He claimed that if he had been so warned, he would not have taken the drug because his acne was not severe enough as to risk such a permanent injury.

As prescribed by Dr. Gerald, plaintiff began treatment for his acne with Accutane on June 22, 1995. He did so after an unsuccessful course of treatment with Bactrim, an antibiotic. Plaintiff received a dosage of 40 milligrams (mgs) of Accutane twice a day, or slightly over 1 mg per kilogram of body weight per day (1 mg/kg/day).*fn6 During that treatment with Accutane, Dr. Gerald monitored plaintiff every thirty days for possible side effects. Plaintiff initially experienced chapped lips, dry eyes, and pain in his knee, but no gastrointestinal effects.

Plaintiff stopped taking Accutane on October 19, 1995, after about four months of treatment and after his acne had been successfully cleared. As of February 6, 1996, plaintiff was not experiencing any side effects.

However, in the summer of 1996, plaintiff began having abdominal pain and diarrhea. As that summer progressed, his symptoms worsened. He experienced stomach cramping, burning diarrhea, and rectal bleeding. Plaintiff was admitted to the hospital in November 1996, suffering from pain, diarrhea, vomiting, and fatigue. He was treated at the hospital for an ulcer, and given a course of antibiotics.

On November 27, 1996, plaintiff was diagnosed with ulcerative colitis. The diagnosis was later changed to Crohn's disease. He was treated with steroids. Around this time, some of the side effects that plaintiff had previously experienced while he was taking Accutane reemerged, including chapped lips and joint pain.

In December 1996, plaintiff underwent a proctocolectomy, a procedure in which his entire colon and rectum were surgically removed and replaced with an ileoanal pouch. He continued to suffer from chronic diarrhea, and had additional surgeries for a rectal abscess. He also was hospitalized for bowel obstructions.

By April 1998, plaintiff's IBD had spread to his ileoanal pouch. He suffered from excessive diarrhea, fever, blood and mucous discharge, abdominal cramping, incontinence and fatigue. To address those persisting symptoms, plaintiff underwent a diverting ileostomy, a surgical procedure in which the small intestine is brought through the abdominal wall to drain into an ileostomy bag. Despite this additional surgery, plaintiff continued to experience problems with incontinence. He had leakage of fecal matter, excess gas and pain. He also claimed humiliation as a result of noises emanating from the bag.

In 2002, plaintiff underwent another surgery, this time to reverse the ileostomy and to reform the ileoanal pouch. The ensuing absence of the ileostomy bag was an improvement, but plaintiff continued to endure a host of complications, including incontinence, pain, cramping, fatigue and diarrhea. On an average day, plaintiff had eight to ten bowel movements during the day, and two or three at night.

These difficulties prompted plaintiff to retain an attorney. The attorney submitted an ADR report on his behalf to Roche. Based upon that information, internal Roche documents entered into the ADVENT database concluded that plaintiff's IBD was possibly related to his use of Accutane. In the CIOMS comments field, Roche indicated that "ulcerative colitis is listed in the CDS [database] for isotretinoin. Based on the information received for [plaintiff's] case, a causal relationship between the reported event and the treatment with isotretinoin is assessed as possible. Company causality is based on the Naranjo algorithm." (Emphasis added).

F. Plaintiff's Lawsuit

On July 23, 2003, plaintiff filed a complaint against Roche, whose principal place of business is in New Jersey. Plaintiff sought compensatory and punitive damages under the applicable product liability laws, as well as economic losses under the New Jersey Consumer Fraud Act, N.J.S.A. 56:8-1 to -20 ("CFA"). Roche filed an answer and separate defenses. Plaintiff subsequently filed an amended complaint, adding a common-law negligence claim.

By order dated May 2, 2005, the Supreme Court designated all pending and future statewide actions involving Accutane as a mass tort, pursuant to Rule 4:38A. All Accutane cases, including plaintiff's lawsuit, were consequently transferred to Atlantic County to be heard on a coordinated basis. Discovery in the state cases proceeded in tandem with discovery in the federal Accutane multidistrict ("MDL") litigation.

Roche made numerous pre-trial motions, including a motion to dismiss plaintiff's complaint as time-barred under Alabama's statute of limitations, motions for summary judgment on the adequacy of its warnings, and motions to exclude the testimony of plaintiff's causation expert. The trial court denied all of these motions.

G. Plaintiff's Expert Proofs

1. Causation - Dr. Sachar

Plaintiff retained as his causation expert David Sachar,*fn7 M.D., a gastroenterologist. Dr. Sachar is board-certified in internal medicine and the past chairman of the FDA advisory committee on gastroenterology. He had been specializing in IBD for thirty years, and has published over 220 articles on IBD, ulcerative colitis, and Crohn's disease. Dr. Sachar is a Professor of Medicine at the Mount Sinai School of Medicine, where he has been teaching since the 1980s.

Dr. Sachar opined that, as a general matter, Accutane in regularly-prescribed doses is a cause of IBD in humans. More specifically, Dr. Sachar contended that Accutane was the cause of plaintiff's IBD.

Dr. Sachar stated that the pharmaceutical industry generally determines whether there is a causal relationship between a patient taking a drug and experiencing an adverse effect by conducting a case controlled, or epidemiological, study. Such studies, according to Dr. Sachar, provide "compelling scientific evidence for a certain factor being a measurably statistically quantifiable risk factor for a certain disease." Because Roche had not conducted such a study with respect to Accutane and IBD, Dr. Sachar claimed that he spent hundreds of hours reviewing other evidence to determine causation.

a. Dog Studies

In reaching his conclusions about Accutane's causation of IBD, Dr. Sachar relied, in part, on animal studies. These studies included a fifty-five week oral toxicity study of Accutane that Roche conducted on beagles in 1979. The beagles were divided into two control groups. They were further divided by three dose levels: (1) high doses (initially 120 mg/kg/day, thereafter lowered to 60 mg/kg/day); (2) mid-doses (20 mg/kg/day); and (3) low doses (3 mg/kg/day). Among other things, Roche scientists learned from this study that:

A variety of gross anatomic changes were observed in the gastrointestinal tract at autopsy and their nature is suggestive of gastrointestinal irritation. The frequency with which these changes were observed is clearly dose related; they were observed in the mid- and low-dose groups only in dogs sacrificed at the end of the study but were observed in some high-dose dogs sacrificed at 30 weeks. These findings and the relatively high incidence of gastrointestinal bleeding in treated dogs suggest that treatment with . . . [Accutane] is associated with gastrointestinal irritation. On the other hand, only one high-dose dog and one mid-dose dog had microscopic findings qualitatively different from unmedicated dogs suggesting that the gastrointestinal changes associated with [Accutane] . . . are neither profound nor irreversible. [(Emphasis added).]

The 1979 beagle study further revealed that high doses of Accutane caused "severe toxicity." Many of the high-dose dogs had what the study described as "signs of gastrointestinal irritation as judged by frequent episodes of black, tarry stools and spots or streaks of fresh blood in the feces." On autopsy, these dogs had an "increased incidence of focal gross lesions in the gastrointestinal tract." By comparison, dogs in the mid-dose group experienced "focal gross anatomic lesions suggestive of gastrointestinal irritation," although not with the same frequency as the high-dose group. The frequency with which blood was observed in the feces of the low-dose animals did not distinguish them from the control group.

Dr. Sachar also reviewed a seven-week oral toxicity study Roche conducted in 1981 on nine dogs. The dogs in this 1981 study were divided into two groups, with six dogs receiving a 120 mg/kg/day dose of Accutane, and three dogs receiving a placebo. The focus of the 1981 study was to determine the location of gastrointestinal bleeding. The treated dogs had frequent visible blood in their stools, and dark tarry stools associated with stomach bleeding. Treatment-related findings included gastrointestinal upset, diarrhea and bloody mucoid stools.

Dr. Sachar explained that it was important to review and consider the results of these animal studies, which are a prerequisite to FDA approval. He opined that adverse effects in animal studies for a drug should raise a "red flag" as to suspected adverse events in humans. Dr. Sachar acknowledged that some of the dog studies had used extremely high doses. However, he contended that such "megadosing" was "good for suggesting mechanisms of action" in humans, even humans taking Accutane at normal doses.

As part of his review, Dr. Sachar took note of animal studies "in which the end products of the metabolism of the drug produced those effects in the animals at concentrations comparable to those achieved in human patients actually taking Accutane the way it is normally prescribed." Thus, he found that some of the animal studies had, in fact, utilized doses "that were actually achieved in human therapy so that there is a direct plausible link [between Accutane use and the reported gastrointestinal symptoms]."

b. Pre-Approval Human Clinical Study

Dr. Sachar also reviewed Roche's 1981 pre-approval study of Accutane conducted on 523 patients. As we have already noted, this study showed that 21.6% of the patients reported gastrointestinal side effects, primarily adverse impacts on mucous membranes. Dr. Sachar testified that this result was to be expected, given his understanding of the biological mechanism of the drug. He explained that Accutane is effective in curing acne because it affects epithelial cells. Epithelial cells line the surfaces of structures throughout the body, including the skin and the entire gastrointestinal tract. Mucous membranes, which line and protect the intestines, are comprised of epithelial cells.

As Dr. Sachar noted, cystic acne occurs when the epithelial skin cells multiply and secrete excessive amounts of mucous and sebum. Although he agreed that the exact mechanism of action of Accutane is unknown, Dr. Sachar posited that the drug affects epithelial cells by inhibiting cell growth and inhibiting sebaceous gland function. He opined that since the intestines are lined and protected by a mucosal lining of epithelial cells, it is biologically plausible that Accutane, which has a "direct toxic effect" on epithelial cells, disrupts the mucosal lining of the intestines, leading to damage. The lining and walls of the intestines would become inflamed as a result of this damage. In some individuals that immune reaction would become chronic, resulting in IBD. Accordingly, Dr. Sachar linked intestinal damage caused by Accutane to IBD.

c. Challenge/Dechallenge/Rechallenge Reports

Dr. Sachar also reviewed over a dozen MedWatch case reports for Accutane containing so-called "challenge," "dechallenge" and "rechallenge" events. A "challenge" occurs when a patient suffers an adverse event while taking a prescription drug. A "dechallenge" occurs when a patient is taken off the drug and the adverse effects are abated, and a "positive rechallenge" occurs when the adverse effects reappear on the drug's reintroduction.

The MedWatch form contains a section asking the drug manufacturer whether the adverse event "abated after use stopped or [the] dose reduced," and whether the "[e]vent reappeared after reintroduction." Dr. Sachar stated these MedWatch reports are taken "very seriously," and are "very important" in determining whether there is a causal relationship between a drug and an adverse event.

For example, in MedWatch Report No. 3379, a seventeen year-old female patient began Accutane treatment in 1995. She stopped in 1996, at that time without incident. In 1997 she recommenced treatment with Accutane. In June 1997, she experienced symptoms of Crohn's disease and stopped taking the drug. By December 1998, her Crohn's disease was in remission. In August 1999, she recommenced treatment, and in September 1999, she once again experienced symptoms of Crohn's disease, including abdominal pain and diarrhea.

Report No. 3470 presented a comparable scenario. It involved a twenty-three year-old male patient who began Accutane treatment in November 1981. After experiencing a "flareup" of Crohn's disease, he stopped treatment in February 1982 and the symptoms subsided. The patient recommenced treatment in May 1983, and his symptoms recurred in June 1983. He ultimately underwent an ileostomy in January 1992, after suffering from weight loss, diarrhea, gastrointestinal bleeding, and anemia.

Dr. Sachar further cited to positive challenge/rechallenge reports submitted for (1) a twenty-three year-old male who developed IBD, (2) a twenty-seven year-old male who developed colitis with bloody diarrhea, (3) an eighteen year-old male who developed IBD, and (4) a thirty-six year-old male who developed bloody diarrhea.

Given these various reports of adverse events, Dr. Sachar opined that Roche should have conducted tests to verify if there was a relationship between IBD and Accutane. He asserted that "whether or not a company chooses to do full-fledged case control studies, it must . . . at a minimum, pay special attention and invest special concern about that issue." He added that "rather than pay special attention to this problem . . . [Roche] as a matter of policy, chose to minimize and downplay this risk and, as a matter of policy, deliberately inhibited the dissemination of this concern to the profession and the public."*fn8

d. Vesanoid Comparison

Dr. Sachar also reviewed side effects reported about users of Vesanoid. Vesanoid is a chemically-similar retinoid manufactured by Roche, which is used to treat acute promyelocytic leukemia ("APL"). Chemically, Vesanoid is tretinoin, an all-trans retinoic acid. Accutane, or isotretinoin, another retinoid, metabolizes into tretinoin and 4-oxo-isotretinoin. Like Accutane, the exact "mechanism of action" of tretinoin is unknown.

The Vesanoid package insert stated that gastrointestinal disorders, including gastrointestinal hemorrhage, were reported in 34% of clinical trial patients. Dr. Sachar opined that these results were significant, because such a high percentage of gastrointestinal disorders would not be expected, even in APL patients. He criticized Roche for failing to conduct an analysis ...


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