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You are here: BAILII >> Databases >> High Court of Ireland Decisions >> Grant v. Roche Products (Ireland) Ltd. [2003] IEHC 17 (25 June 2003) URL: http://www.bailii.org/ie/cases/IEHC/2003/17.html Cite as: [2003] IEHC 17 |
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Record No. 1999 6119P
Between:
Plaintiff
Defendants
Decision of the Master of the High Court on the 25th day of June, 2003
In a letter to the Irish Medical News (March 15, 1999) the defendants wrote that
In the years following the product's launch in 1983 (as "Accutane" in the US; as "Roaccutane" in Ireland) the manufacturers received adverse reaction reports from users and their medical advisers. These "ADR's" were forwarded to the US Federal Food and Drug Administration (hereinafter, "FDA") and were the subject of in-house and independent assessment by the medical/scientific community. Mood swings, depression, and suicidal ideation all featured in the list of side effects reported, along with headaches, dry eyes and other problems."Roaccutane is a uniquely effective therapy for patients with cystic or severe acne which has failed to respond to other treatments. It has been available for seventeen years and is licensed by authorities in over 90 countries. Roaccutane has been prescribed to an estimated nine million patients worldwide with excellent results. Some 2,500 patients have been treated-in Ireland alone in the past twelve months."
"In rare occasions, neuropsychological problems have been recorded (behavioural difficulties, depression, convulsions and suicide attempts)."In February 1998 the FDA required Roche New Jersey to change the US label on Accutane to include the following:
"WARNINGS
Psychiatric Disorders: Accutane may cause depression, psychosis and rarely, suicidal ideation, suicide attempts, and suicide. Discontinuation of Accutane therapy may be insufficient; further revaluation may be necessary. No mechanism of action has been established for these events (see ADVERSE REACTIONS).
ADVERSE REACTIONS
The FDA requires labelling to be changedIn 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 (see WARNINGS)."
Diane Wysowski of the FDA confirms that, ranking all drugs with reported side effects of depression and suicide, "pre 1998, Accutane was number 7 for serious depression". In February, 1997, although his acne had been improving with usage of Minocin over the previous couple of months, Liam Grant Junior was prescribed Roaccutane. Although the word "depression" is not amongst those used in the particulars to describe the young man's subsequent behaviour, he appeared to his family to become withdrawn. Significantly, perhaps, the dermatologist (seventh named defendant) noted of his demeanour on his visit to her in early June that he was happy with the results of the prescribed drug. His family saw something of a personality change. They could be forgiven for thinking that it might not be unrelated to the 2nd year university exams scheduled soon thereafter. He was not himself. However, nothing could have prepared the family for the shock of his suicide on the 15th June, 1997. He was 21 years of age and left an older sister and two younger brothers. The search for the cause of his suicide which began in June, 1997 now leads to these proceedings. This is an action for damages for wrongful death brought by the father on behalf of all dependants of the deceased. (Although exemplary damages are sought, it would appear that s.7 of the 1961 Act precludes any such award.) The Court is asked to determine the cause of the suicide. Causality is central to this case and indeed to most cases. The Court will not embark on an inquiry to determine the truth or falsity of any allegation which is not"to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug: a causal relationship need not be proved".
material and features logically in the chain from cause to effect. Want of care, on the part of any of the defendants, in respect of a matter which played no direct role in the suicide, even though it might be illegal, will not ground an award of damages. Unless the plaintiff can prove, on the balance of probabilities, that the prescribed drug caused the death, the Court will not begin to examine the allegations of want of care on the part of the defendants. (Indeed, if this is a transaction to which the strict "no fault" liability of a producer/manufacturer applies, the Court's enquiry will end there.) If it caused the suicide the court will seek to adjudicate only as to those allegations of carelessness which concern causality. Non causal want of care will not be examined.
The plaintiff has himself seen the distinction between causal and non-causal and alleges want of care, in various respects, on the part of the manufacturer, the Irish Medicines Board, and the dermatologist but is not alleging that the negligence of the Medicines Board caused the death.[For some reason, which is unclear to me, the plaintiff also alleges breaches of warranty on the part of the manufacturer. Warranties are only found in the law of contract, and no contract is alleged as between the deceased and the manufacturer. The fact of "purchase" is pleaded. The plaintiff pleads that the manufacturer made certain misrepresentations to the deceased, but perhaps appreciating the difficulty of proving inducement, given the circumstances, does not include in the prayer any claim for damages for misrepresentation/deceit or for breach of warranty/contract.]Perhaps the plaintiff's case should be formulated on the basis that, taken as a whole and indivisible product, the drug together with its labelling and-prescriptive conditions, was not "safe" in that it should have highlighted the warning symptoms enabling the patient himself to discontinue ( before worse occurred) if it became a
And in some States in the US there is a statute based presumption (albeit rebuttable) that an FDA approved or prescribed warning or instruction is adequate."In a failure to warn context we impose on the plaintiff a very low threshold of proof in order to impute to a manufacturer sufficient knowledge to trigger the duty to provide a warning of the harmful effects of its product. The plaintiff need not prove that the defendant manufacturer was cognizant of a defect, but rather that knowledge of the defect existed within the relevant industry."
The plaintiff has amassed a considerable volume of material and information concerning the history and results of the use of this drug over the years. This material is not evidence in any sense, but was of use in informing the Court as to the content, scientific and statistical, of the controversy surrounding the drug. It was of assistance to the Court, and the Court should not be too "precious" or technical to consider itself unable to make reasonable use of such material however unorthodox the method of its production to the Court. Is there any answer to the comprehensive weight of the defendant's statistical evidence (and the fact that the drug is still FDA approved) quoted above?"The presumption that the duty to consumers is met by compliance with FDA regulations helps to ensure that manufacturers are not made guarantors against remotely possible, but not scientifically verifiable, side effects of prescription drugs." (Perez 161 NJ 25).
In the British Journal of Dermatology for 1999 (nine years later), L. G. Millard submitted the following under the heading "Adverse mood and behaviour change in young patients on systemic isotretinoin"."Discussion. The results of this study suggest that depression is a rare side effect of isotretinoin that was spontaneously reported in 7 of approximately 700 patients. In these patients the onset of depression was related to neither dosage nor time. Irrespective of dosage, all depressive symptoms rapidly resolved within 1 week of cessation of medication. On the basis of the patients' psychiatric history, the development of a major depressive episode in all seven patients in this study most likely represents an idiosyncratic side effect of isotretinoin rather than a predictable effect in a subset of patients predisposed to develop major depressions."
"Ever since the first reports of acute depression from isotretinoin in 1990 there has been continuing debate as to whether this represented a real drug side effect or mental health 'background noise' in a population of young patients where 6.1 % of persons 15 - 24 yrs. old experience major depression compared to 4.9% of the general population (Am J Psychiatry 1994: 15:979-86)
A retrospective study of 38 young (13 - 24 yrs.) patients who had received systemic isotretinoin for acne and who had no evidence of
significant pre-treatment depression or behaviour change (HAD Scale) identified 6 patients (4F.2M) who developed major psychiatric symptoms during treatment (HAD Scale p. 0.01) Depression occurred early in 3 and later in 1 patient whilst aggressive destructive antisocial... (?) developed in 2. The depression was notable for the acuity of onset, the severity and the profound sadness and despair ... patients recovered in 4-6 weeks after stopping medication. Two patients were given Prozac. There was no recurrence of psychiatric illness on follow up in 18 months.
In the aftermath of an RTE Prime Time broadcast in November, 1998, the defendants issued for publication two letters to RTE from authoritative specialists (Harvard, Columbia respectively) who had been engaged by the Roche companies to consider all the ADR's, review the literature, and offer an independent and objective opinion for the purposes of a presentation to the FDA. Dr. David Bickers stated that:Systemic isotretinoin appears to cause a small but real increase in serious psychiatric morbidity which needs ... identification at clinic review by simple oral questionnaire."
"My scientific opinions to the FDA were that (1) there is no evidence that any retinoid affects biochemical pathways in the human brain which are thought to be involved in depression; (2) there is no evidence of an association between psychosis, depression, attempted suicide or suicide and Accutane; and (3) the effects of hypervitaminosis A on psychiatric disorders have not been well documented. Although retinoic acid is related to Vitamin A it is important to note that Accutane is a less potent synthetic analogue.
My opinions to the FDA were that (1) Accutane is the single most effective drug for the treatment of severe recalcitrant nodular acne and (2) acne is a potentially devastating disease which can result in permanent physical and psychological scarring."
"After reviewing all the case reports and the professional literature, it was my opinion that there is no causal relationship between Accutane and depression/suicide. The suicide/depression reported in the cases are consistent with epidemiologic and clinical findings (a preponderance of suicide in males and a preponderance of depression in females). Also, the number of suicides reported in this at risk population (young persons with self-esteem problems due to a physical abnormality) was far beneath what one would have expected in this population. It is known in the field of suicide that when suicide does occur in young persons it is not unusual for the families to not be aware of underlying depression and/or despair and to be surprised by the suicide.
The depression described in the case reports did not contain enough clinical information to satisfy the criteria for clinical depression. In addition, very few of the cases described required specific psychiatric treatment. Moreover, since the majority of persons who kill themselves do so on the first attempt, it would not be unusual to have cases where a person killed themselves on the first attempt.
After extensive review of the literature I could not find any information that described a biological mechanism between the reported relationship between Accutane and depression/suicide. My analysis of the suicide reports revealed that they were consistent with the clinical phenomena of suicide - presence of psychiatric illness, family history and family problems. There was co-medication and other confounding factors, there were multiple scenarios, and there was a weak temporal association. Thus, it was my conclusion after review of the case reports, professional literature and my own academic and
But this impressive expertise is not without its critics. Reviewing the apparently similar, if not identical, material submitted by Roche to the FDA in the run-up to the imposition of the new labelling in 1998, the FDA's own Dr. O'Connell commented to the effect that the 11 reports of suicide attempts "from 1996 and 1997 alone", read in the knowledge that "spontaneous adverse event reporting decreases over time after approval", suggested that a much higher actual number of unreported attempts was likely for those years. Examination of some of the ADR's, especially those reporting "de-challenge and re-challenge" (i.e. coming off the drug and going back on later), he found "robust" examples including one psychosis report which "in this reviewer's opinion would strongly suggest causality" (also referred to as "product/event association"). He cites Duke (1993) noting "two cases assessed as evidence of severe psychiatric and psychological reactions to isotretinoin" and observing that "recently groups of cases have appeared, suggesting that these side effects may not be the rarity they were initially considered to be." There might be validity also in analysis which rejects the general population as a benchmark against which to test the incidence of side effects of oral isotretinoin on the basis that the users of the drug have, unlike many who seem incapable of tackling personal crises, taken the first step (and, we are told, will be happy with the results of the treatment) and are, ipso facto, less likely to commit suicide. Fifty year olds, who are likely to be the most stable and untroubled cohort in society, are going to look for explanations if an otherwise inexplicable rise in the incidence of suicide can be linked to a particular year's production of Cuban cigars. "The wrong people are committingclinical experience with suicide that there was no causal relationship between Accutane and depression/suicide."
suicide", they will cry, "none of us has reason to be depressed." In a sense Roche's own statistical data suggests just such a theory: Accutane has a beneficial effect on the psyche; acne sufferers who might otherwise have entertained suicidal thoughts are uplifted. The suicides of a few, previously free of depressive symptomology, is against the odds for a cohort enjoying a relatively positive phase in life. The "wrong" people are dying.
The question is not whether Roaccutane caused the suicide but whether it is more probable that it was caused by Roaccutane than by some other circumstance personal to the deceased. He was the victim of one of two remote possibilities. On the one hand, some proof of the possibility that he was the victim of a side effect of Roaccutane may be available, (but only inferentially, and not in the concrete form of a "description of a biological mechanism" which Dr. Jacobs could not find) from the science, though its weight may be significantly diluted by the preponderance of statistical evidence contrariwise. On the other hand, it may be even less likely that this young man would have let some unknown circumstance (however apparently important) drive him over the edge. His family certainly feel he was made of sterner stuff. Doubtless, in time, the Court will examine both possibilities. Regarding the opinion expressed to the FDA in 1998 that there is "no evidence that the pharmacologic effects of retinoids influence serotoninergic or dopamine pathways in the human brain", Dr. O'Connell offers scientific references whichidentify respectively involvement of genes of the retinoid (vitamin A) system in the etiology of schizophrenia, retinoid pathology indicated by congenital anomalies in relatives of schizophrenic probands, a role for retinoic acid in distinguishing dopamine D2 receptors, detrimental effects of such acid on some neuroblastoma cells
and rat mid brain neurons, and (a 1998 reference) clear support for the involvement of retinoic acid in dopaminergic signalling in adult murine and human brain.
Dr. O' Connell's overall view at that time was that:"Given all the pieces of evidence available, it is difficult for me to. avoid the conclusion that Accutane can adversely affect the adult brain in clinically significant ways and that Accutane use is associated with severe psychiatric disease in some patients ...
The emerging science linking retinoid receptor biology with dopaminergic regulation may ultimately inform an understanding of the neural pathways, altered by exogenous retinoid administration, and provide support for causality...
This, then, is a case in which the scientific issues (including the interpretation of the statistics) will not be determined on anything other than the opinions of experts. It seems somewhat ironic that, in an action in which the plaintiff complains thatThe rapid resolution in many of the reported dechallenge cases suggests that an educational message to practitioners and their patients may prevent significant morbidity, and hopefully mortality."
Roche were negligent in that they:
once confronted with the product of such studies he attacks the independence and honesty of the expert. (He has furnished me with, inter alia, the documents pertaining to his professional complaint against Prof. Cunliffe of the General"failed, refused and neglected to undertake and carry out any or any adequate studies/research into the association between the drug known as Roaccutane and depression, psychiatric disorders, suicide (sic) ideation and suicide or in the alternative failed to publish any or any adequate results of any such study,"
Infirmary, Leeds, a complaint which was twice rejected.) Nor is his case assisted when he writes to a professor in Galway (7/l/03) to the effect that "Roche categorically refused to provide the information and I took legal proceedings to try and force disclosure" (copy furnished to defendants' solicitors). In fairness to him, of course, he must be understandably angry at the needless death of his eldest son. Perhaps, however, he ought to take some time out to calmly consider all of the "evidence" he himself has assembled, (as I have). He knows what he knows: the probability that the death was a side effect of Roaccutane. A freak accident (in statistical terms) for which Mother Nature is to blame. And even if the drug as prescribed had come with clearer warnings, what matters now is whether he can establish as a probability that his son would have read, recognised and acted upon such advice, (especially given that he was so keen to clear up his spots) if he identified the specified contraindications as referable to himself ?. These are the sorts of issues (along with other aspects of his son's life and society) that the Court may ultimately have to grapple with: After all, the questions the-Court has to try to answer are "why did he kill himself?", and "on the balance of probabilities, would any extra care on the part of any of the defendants have ensured or contributed to a happier outcome?".
It will be hard to forgive the sixth defendant's crass insensitivity in denying that the deceased's family "suffered the mental stress (sic), loss, damage and expense as alleged", especially as there is no dependency claim and the only special damage pleaded is the cost of the funeral and headstone. The Roche defendants cannot be faulted in this regard. Indeed, in their prelitigation correspondence with the plaintiff and in their response to the request for discovery with which the Court is now concerned, these defendants have been more than co-operative, taking a broader andconcerned, these defendants have been more than co-operative, taking a broader and more non-technical view of discoverability (and its intrinsic constraints of relevance, materiality, necessity and cost) than would be appropriate under the Rules of Court.
A consent order has been made in respect of most of the categories.These defendants have agreed to discover much of what is sought, but decline to go further in a number of respects. This stance could lull the Court into approaching the question of discoverability of the additional material on the basis of its similarity with material agreed to be discovered or on the basis of the relatively small additional burden which discovery thereof would impose. These are not, per se, the appropriate considerations. I'm not authorised by the defendants to be more generous with their material than they have been. I can only order discovery where the law entitles the plaintiff to same. Likewise I cannot excuse the defendants from additional discovery on the basis of the quantum of material already agreed to be discovered - if any of the additional documentation is discoverable (and I include in that term the concept of necessity which, of course, must be tested having regard to the material agreed to be discovered) discovery will be ordered.
The main area of dispute between the parties concerns material which is other than CNS specific. The plaintiff would like everything in the files about all and any adverse reports, whether they concern the Central Nervous System or not. It is the defendants' submission that no material is relevant, in the context of depression/suicide side effects, apart from CNS documentation. I think the defendants are correct. Whether you start your analysis with depression/suicide and work back into the relevant mechanisms and workings of the body, or whether you start with oral isoretinoin (or excess Vitamin A) and trace its travels through the human system, you arrive at the CNS. From whichever direction,you arrive at the CNS. I can see virtually no reference to any other part or system of the body in any of the great body of scientific material I have been given to read. On the contrary, the material is so replete with references to CNS that one is forced to conclude that the scientists concerned (who are uniformly precise and accurate in their use of language) would be surprised at the suggestion that they had overlooked other areas relevant to their inquiries.
The same FDA Dr. O' Connell refers to "other CNS adverse events noted in the reports I have reviewed include ... " and "The reported effects on the CNS are not surprising." His conclusion above cited refers to support for causality from "anunderstanding of the neural pathways."
I have read Dr. McLane's description of the process involved (per transcript of evidence) in the following terms:That seems to closely echo the language of a 1994 Swedish study (published by Pergamon) by Zetterstron et al entitled "Localisaton of Cellular retinoid binding proteins suggests specific roles for retinoids in the adult central nervous system" (my emphasis), in which the authors, stating as the starting point of their analysis the theory that "retinoic acid, the active metabolite of retinoids (vitamin A compounds), is thought to act as a gene regulator via ligand activated transcription factors", the"Isotretinoin is a natural endogenous compound that is found normally in every person. Isotretinoin is a natural ligand for some retinoid receptors. Isotretinoin has another name called 13-CIS-retinoic acid. The all-trans-retinoic acid has much better binding properties to these ligands than the 13-CIS does. Once the retinoid binds to the receptor, this type of receptor is a receptor that binds directly to DNA on the signalling mechanisms on genes, and it activates particular genes."
authors open their "discussion" with the comment that "surprisingly little is known about the possible risk of retinoids in the adult CNS." (my emphasis)
The authors localised cellular retinol binding protein type 1 and cellular retinoic-acid binding protein type 1 and reported that most of the immunoreactivity is neuronal, with very strong cellular retinol-binding protein type 1 in the dendritic layers of the hippocampal formation. And this from the abstract of a paper by McCaffrey & Crendall "Influence of Retinoic Acid on Hippocampal Cell Division":The Oxford English Dictionary tells me that the Hippocampus has as meaning No. 2 (anatomical) "the elongated ridges on the floor of each lateral ventricle of the brain, thought to be the centre of emotion and the autonomic nervous system". And the autonomic nervous system? It means "the part of the nervous system responsible for control of bodily functions not consciously directed, e.g. heartbeat". The neuropharmacologist in Galway, to whom the plaintiff wrote recently in the terms above criticised, when specifically requested to provide written support for unlimited discovery in this case, wrote of his present work in the area of immunology:"Numerous clinical reports have associated the use of the oral acne drug Accutane (Isotretinoin, 13-CIS retinoic acid, RA) with effects on the central nervous system (my emphasis) which include headache and depression. Roaccutane is known to enter the central nervous system and act as a potent transcriptional activator, and so it is likely that RA can influence brain function. One hypothesis for the underlying cause of human depression is that it results from a loss of hippocampal neurons. Chronic exposure to RA may be expected to cause a similar state."
"Activation of the immune system produces a variety of physiological effects that resemble a depressive episode."
(Roaccutane activates the immune system: hence its curative properties vis-a-vis acne.) He goes on:
"Studies suggest that investigation of peripheral ADR's can be important in trying to ascertain the mechanism associated with CNS alterations" (my emphasis), and
"In my opinion, any information available on circulating levels of immune and endocrine components would be particularly worthwhile, where they exist for patients who have presented with CNS problems"
The plaintiffs application for documentation in- addition to CNS related documentation is spread over nine of the nineteen categories sought. I am of the view that he is not entitled to discovery. Going by the frequency of references to the CNS in the scientific material and the infrequency of references to other systems in the body (and also because this is a case of suicide following apparent symptoms of mental distress), I am of the view that only the CNS related documents are relevant. If I am wrong in that conclusion, I have then to review each of the said categories, in the usual way, to check for relevance, materiality and necessity. I have to review the pleadings and the stated reasons for the request for discovery of documents in each such category. They are categories 2, 3, 5, 6, 7, 8, 11, 12, 15. If I decide that there is no basis for the additional discovery sought, more often than not there will have been no basis in law for the discovery (CNS related) already agreed to by the Roche defendants: a curious outcome!(again, emphasis added.)
some discovery even if they have (in the context of CNS related documentation) offered more than they are obliged to. Their offer to discover does not alter the criteria for discovery: these are determined by the applicable law.
So then, back to law at last! Category 2 is about the defendants (in 1997) knowing that (or not taking appropriate steps to find out if) Roaccutane was dangerously defective, being a careless manufacturer and not (significantly) minimising the adverse side effects. Category 3 is for the purpose of discovering third party research material known to the defendants (pointless to ask for discovery of material of which they ought to have know but didn't - if they have it to discover, they know of it!) . Categories 7 and 8, for the identical reason, seek complaints and correspondence concerning adverse reactions because, the plaintiff alleges, the defendants knew it was not safe etc., and (presumably - he doesn't say so) this documentation might assist in the proof of this allegation. In a strict liability context, the plaintiff is not on proof of fault. Even in the Common Law it is not an essential proof for the plaintiff to demonstrate that the defendants knew the product was unsafe. It is an alleged fact (and denied), but it is not material. If I am wrong in this also, I say that discovery is unnecessary as it is patently obvious, starting with the labelling on the product, that the defendants knew of the industry's concern about side effects. Category 5 (worldwide ADRs) is sought by reference to the plaintiff's allegation that the defendants knew ... etc. See ratio above. The ADRs are also sought by reference to the allegation that the defendants failed to inform doctors (or the deceased) adequately in relation to adverse reactions.point. In any event, there is ample evidence of many deaths amongst users of the drug. I refer again to the statistical material above recited.
The second major area of resistance to discovery by the defendants is their objection to discover anything post (early) 1997. A number of categories are in the frame in respect of this limitation. These are 1, 5, 6, 7, 8, 16, 18. For the reasons above stated I am not ordering discovery in respect of categories 5, 6, 7, 8. The reasons advanced for category 1 all refer to either representations made to the deceased, or negligence which caused damage to the deceased. Clearly, the facts which the plaintiff wishes to prove all predate the death. Proof that in another jurisdiction, at a later date, the terms of the warning supplied to the patient or physician were more explicit, or helpful, is not probative of a want of care in Ireland in early 1997. It may be suggestive of such, but the plaintiff will have to base his case on stronger evidence, augmenting such probative evidence with corroborative non-Irish material. The plaintiff supplemented his request for voluntary discovery (21/5/02) with a letter (11/9/02) responding to the defendants' offer of limited discovery (12/7/02). In turn, this was replied to on the defendants' behalf (7/11/02). In respect of this category he suggests that he would like to prove that tests/research subsequent to the death were "of a nature which the defendants could easily have carried out before the death." Clearly none of this research has produced results which have caused the drug to be withdrawn from the market. It is perhaps suggested that labelling changes alone may point to carelessness in the research basis for and the compilation of the earlier label, and that label changes may be evidence of the incorporation of new research. As such this category is but an alternative route to other categories, and not itself productive of probative evidence.just how extensive is the material available in this mater in the public domain (by internet, presumably) and as furnished directly by the defendants. On this basis also (documentation in the public domain) the plaintiff s application fails on grounds of necessity having regard to the issues in the case, and not the wider range of matters which the plaintiff might wish the Court to consider, acting as a quasi-investigator. The issues which the Court will determine are quite net.
In short, therefore, the supplemental discovery sought must be refused on any one of a number of different bases. The stated reasons are inadequate. The issues are not material. The documentation is not probative. The discovery is unnecessary.
