An Inquest taken on behalf of our Sovereign Lady the Queen at Adelaide in the State of South Australia, on the 27^th, 28^th and 30^th days of July, 1998, 29^th, 30^th and 31^st days of May, and 9^th day of June, 2000, before Wayne Cromwell Chivell, a Coroner for the said State, concerning the death of Maria Tzanavaras.

I, the said Coroner, do find that Maria Tzanavaras, aged 64 years, late of 28^th Street, Renmark, died at St. Andrews Hospital, Adelaide, on the 7^th day of March, 1996 as a result of submassive liver necrosis secondary to drug (Coumarin) toxicity. The circumstances of death were as follows:-

1. Introduction

1.1 Mrs. Maria Tzanavaras died on 7 March 1996. This inquest commenced on 27 July 1998. On 30 July 1998 Mr. Kourakis QC, who then appeared for the Tzanavaras family, sought an adjournment of the inquest in order to call further evidence. This was granted. For a variety of reasons, too convoluted to outline here, I regret to say that it has not been possible to resume the inquest until now. This has not been due to the fault of any party involved, but such delay is undesirable for obvious reasons, and I express my regret to the participants that it has occurred.

1.2 Mrs. Tzanavaras developed breast cancer in 1984, and was referred by her general practitioner to Mr. L.L. Hoare in Adelaide. Mr. Hoare is an eminent general surgeon. On 30 October 1984, he performed a modified radical mastectomy on the right side.

1.3 There was no sign of recurrence of the cancer, but unfortunately Mrs. Tzanavaras developed lymphoedema, caused by problems with lymphatic drainage of the right arm following the surgery. Mr. Hoare, quoting the Royal Australian College of Surgeons’ monthly journal for March 1998, described this as a "reasonably frequent complication" (T.176).

1.4 Lymphoedema is a condition caused by the inability, through surgery or otherwise, of the body to drain fluid through the lymphatic system. This results in painful swelling of the tissues, fibrosis, susceptibility to infection, loss of mobility and utility of the affected limb. This often results in severe psychological stress to the patient and even suicide. In some cases the condition is so severe that the limb must be amputated. The chronic condition is some cases has led to a particularly lethal form of cancer or angiosarcoma called Stewart-Treves syndrome (see the evidence of Dr. Judith Casley-Smith, T.327-333).

1.5 This condition caused Mrs. Tzanavaras’ right arm to become swollen, and caused her great discomfort. Mr. Hoare noted her complaints in 1987, and again in 1989 (T.161). He referred her to a physiotherapist, Mr. Michael Mason, in 1991. Mr. Mason had developed an expertise and special interest in treating this intractable condition, but she did not undertake the extensive course of treatment he recommended. The fact that she lived in Renmark was one complicating factor.

1.6 On 26 September 1995 Mrs. Tzanavaras saw Mr. Hoare again. Her son John, who usually accompanied her and helped if there were any language difficulties, showed Mr. Hoare an article in "The Advertiser" about a new drug called "Lodema". John asked him about it and Mr. Hoare told him that he had prescribed it to several other patients with good effect, and that there had been no untoward side-effects (T.10). He also pointed out that if Mrs. Tzanavaras noticed any side-effects, or felt "crook", she should stop taking the drug immediately and advise her general practitioner (T.164, 184). Mr. Hoare gave her a prescription, with several repeats, for the drug.

1.7 Mrs. Tzanavaras began taking Lodema in October 1995. John Tzanavaras said that the family noticed a significant improvement in her arm for the first month or so, but the improvement faded after that. His mother became lethargic and nauseous. She ceased taking the medication and consulted Dr. Sidhu, who took blood tests, and sent her to Mildura for an ultrasound scan. Following results of these tests, he referred her to St. Andrews Hospital in Adelaide to see Mr. Hoare. Mr. Hoare immediately referred her to Dr. Hugh Harley, the Head of Hepatology at the Royal Adelaide Hospital and Senior Visiting Medical Specialist in Hepatology at the Flinders Medical Centre. Dr. Harley saw Mrs. Tzanavaras at St. Andrews Hospital.

1.8 Dr. Harley saw Mrs. Tzanavaras on 12 February 1996 and noted a three-week history of loss of appetite, nausea, vomiting, lethargy, dark urine, mild fever and headache. She was visibly jaundiced (T.65). She said that she had stopped taking the tablets when she first felt unwell. Dr. Harley diagnosed a severe liver injury, although he did not, at that stage, identify the cause. He

said that he was suspicious of Lodema, being aware of two other cases in South Australia in the previous twelve months where Lodema had caused liver toxicity (T.37). He regarded a toxic drug reaction as the "principal differential diagnosis" (T.38). This diagnosis was assisted by Dr. Sidhu’s tests, which excluded malignancy, gallstones and other pathology. Dr. Harley said that these tests, and subsequent referral to a specialist, had been done with "good speed" (T.40).

1.9 On 19 February 1996 Mrs. Tzanavaras lapsed into a coma because of liver failure, and, apart from one occasion when she regained consciousness, remained comatose as her condition steadily deteriorated until she died on 7 March 1996.

2. Cause of death

2.1 With the consent of the family, Dr. Harley performed a liver biopsy following Mrs. Tzanavaras’ death. The results of the biopsy are in the St. Andrews Hospital casenotes (Exhibit C.8). The histopathologist reported the presence of "mild to moderate degree of liver collapse due to hepatocyte necrosis with no significant inflammatory response, ? cause, ? ? Coumarin induced". Dr. Harley commented that the "weight of probabilities" implicated Coumarin (the scientific name for Lodema), although this could not be stated with "100 percent certainty" (T.75).

2.2 Dr. Harley wrote a death certificate for Mrs. Tzanavaras which outlined the cause of death as "spontaneous bacterial peritonitis, ascites due to liver failure, with a history of carcinoma of the breast". He did not report the matter to a coroner or police officer pursuant to Section 31(1) of the Coroners Act, which reads:-

"A person knowing of, or becoming acquainted with, the finding of the body of a dead person, or the death of a person apparently by violent or unusual cause, must immediately notify a coroner, or a police officer, of that finding or death".

 

Dr. Harley said that he did not regard the case as "unusual", particularly for a hepatologist. He acknowledged, as I do, that "unusual" is a rather vague expression (T.50). Dr. Harley conceded that he had never seen a death related to liver toxicity due to Lodema or Coumarin before (T.86).

2.3 Dr. Harley said that he always intended to report the matter to the Adverse Drug Reactions Advisory Committee (ADRAC), which, he said, has the "pivotal" regulatory role in relation to the safety of drugs (T.49). I will discuss the role of ADRAC in more detail later.

2.4 Of course, because Dr. Harley did not report the matter to a Coroner, no post mortem examination was directed pursuant to Section 13(1)(e) of the Coroners Act. Dr. Harley said that he did not think that a post mortem examination would have established the cause of death with any greater precision. He said:-

"No, the liver biopsy has taken it as far as we possibly can to determine the nature of the liver injury, which I believe was the initial event in this cascade and as I pointed out, we have evidence that there is some massive (submassive) hepatic necrosis. This is a pathological diagnosis, just to say that there are a lot of liver cells that have died out. There has been some collapse of the framework of the liver and in areas the liver cells have dropped out but we can’t be in any way more specific as to the precise cause of that injury. A post mortem or autopsy may have confirmed the nature of any accompanying renal or pulmonary pathology but would not have determined in any more, with any more accuracy the precise cause of the liver injury which seemed to have been the initiating event. Just to add to that, there’s no toxicological way of being more certain about this. I think there’s no question that the drug was totally washed out of her body by the time Mrs. Tzanavaras presented to me in February. The problem is the injury had been done to the liver and the injury in this age group is very slow sometimes to repair, we call it ineffective regeneration of the liver. A younger liver has a greater ability to regenerate than an older liver does".

(Exhibit C.3, p4).

2.5 Even allowing for the vagueness of the term "unusual" in Section 31 of the Coroners Act, in my opinion Dr. Harley was in error in failing to report Mrs. Tzanavaras’ death to a coroner. I accept that, in his position as a leading hepatologist, he is likely to see more unusual cases of liver toxicity in the course of his practice than a medical practitioner with less specialist expertise would. But even allowing for that, it seems to me that a case involving a drug available on prescription, registered under the Therapeutic Goods Act, causing a fatal liver toxicity, was sufficiently out of the ordinary to justify reporting it. The failure to report it could well have denied the family of the deceased the opportunity to have her death fully investigated.

2.6 The matter came to my attention because, on 18 March 1998, Dr. Harley signed a claim form to an insurance company giving the cause of Mrs. Tzanavaras’ death as "submassive necrosis of the liver secondary to drug (Coumarin) toxicity". When the family realised that Dr. Harley felt that the Lodema was implicated in Mrs. Tzanavaras’ death, they reported her death to me, and an investigation was undertaken.

2.7 The circumstances of Mrs. Tzanavaras’ death are clear enough, even without a post mortem examination, and I therefore find that the cause of Mrs. Tzanavaras’ death was submassive liver necrosis secondary to drug (Coumarin) toxicity. I note that counsel did not suggest otherwise.

3. The legal status of Lodema

3.1 Dr. Leonie Hunt was, in 1998, the Acting Director of the Conformity Assessment Branch of the Therapeutic Goods Administration ("TGA"). In very general terms, her job includes the assessment of drugs for registration under the Therapeutic Goods Act. Dr. Hunt said that she first became aware of the drug, then called Coumarin, in 1986. She understood that it was initially manufactured by Dr. John Casley-Smith in his laboratory at the University of Adelaide, and later by Hamilton Laboratories (T.98). This was confirmed by Mr. Richard Blake, the Managing Director of Hamilton Laboratories. Mr. Blake said that the company was approached by Dr. Casley-Smith, who was world-renowned as a researcher in the field of the human lymph system, and he asked the company to put the drug Coumarin in tablet form to be used in clinical trials that were then being conducted (T.232).

3.2 The Therapeutic Drugs Act 1989, and Regulations came into force in 1991. Because Coumarin had been available before this time, it was "grandfathered" into the poison schedule at level 4, without the need for a full assessment.

3.3 The Lymphoedema Association of Australia Inc. ("LAA") sponsored the registration of the drug. The prime-movers in that organisation were Dr. John Casley-Smith and his wife, Dr. Judith Casley-Smith.

3.4 As the sponsor, LAA conducted the bulk of the dealings with the TGA concerning the drug and its registration. In early 1994, it was decided to seek to introduce the tradename "Lodema" to avoid confusion with other products with similar names. In the course of that application to the TGA, clinical data was requested to establish the efficacy of the product in order to verify information on the product labels.

3.5 In mid 1994 Dr. John Casley-Smith made Mr. Blake aware of an article by Cox, O’Kennedy and Thornes in Human Toxicology (1989).8.501-6 (the Cox study), which described the incidence of Coumarin causing elevated liver enzyme levels at 0.37 percent, or 37/10,000. This hepatitis was described as "probably a form of idiosyncratic hepatotoxicity", which may have been immune in origin.

3.6 ADRAC had, by mid 1995, assembled a total of ten cases where an adverse reaction to Coumarin had been reported in a period of fourteen months, of which six were adverse hepatic reactions, and one had been fatal. These reports were reported to the Australian Drug Evaluation Committee ("ADEC"), the members of which had become concerned that the Product Information for the drug was inadequate.

3.7 There had been correspondence between LAA and TGA in late 1994 about the Product Information for the drug. The Product Information was amended by Dr. John Casley-Smith in November 1994 to contain the statement:-

"A small number of patients develop elevated liver enzyme levels. This is probably an idiosyncratic hepatitis which is reversible on discontinuation of therapy".

(Exhibit C.9c).

A similar statement appeared under the heading "Adverse reactions" in the 1995 MIMS Annual, the prescribing guide used by most medical practitioners in Australia.

3.8 A letter had appeared in the Medical Journal of Australia ("Med.J.Aust.") in December 1994 from Dr. A.P.A. Beinssen, raising the issue of hepatotoxicity from Coumarin. Dr. Beinssen’s patient recovered on cessation of medication, although she remained unwell at fifteen weeks (Med.J.Aust.161:725). It was as a result of this report that Dr. Hunt initiated the changes to the Product Information referred to above.

3.9 Dr. John Casley-Smith wrote to the Medical Journal of Australia in April 1995 defending Coumarin, and referring to the Cox study which described the hepatic side-effects as "rare". He referred to extensive trials he and his colleagues had conducted which confirmed the incidence of side-effects at 2/1106 (0.18 percent), which he argued was similar to that found in the Cox study. He argued that only four out of 2,173 patients in the study suffered toxicity which could be directly linked to Coumarin (0.18 percent). Dr. Casley-Smith also reported that in over 300 other clinical trials of Coumarin, involving some 20,000 patients in other countries, hepatotoxicity was absent. Since July 1993, when Coumarin became "generally available in Australia", he pointed out that there had been four incidents of hepatotoxicity in 1,750 patients (0.22 percent), although "one patient was an alcoholic". Dr. Casley-Smith concluded his letter saying:-

"No special precautions seem indicated when taking oral Coumarin. However, liver function tests should be performed if the patient has symptoms suggesting hepatitis, and the drug should be withdrawn if results are abnormal."

(Med.J.Aust.162:391).

3.10 At its meeting on 8-9 June 1995, ADEC noted that the incidence of hepatotoxicity from Coumarin noted by ADRAC in the past fourteen months was 0.34 percent compared with the figures propounded by Dr. Casley-Smith referred to above. At that meeting ADEC decided to review the data at its August meeting, and "recommend appropriate action". They also gave notice that:-

"The company should be advised that the currently registered Product Information is inadequate, both in terms of content and presentation, and will require extensive revision".

(see Exhibit C.4a, p1-2).

3.11 In July 1995, Dr. M.L. Bassett wrote to the Medical Journal of Australia advising of the death of a patient from liver failure. The patient had been ill for seven weeks after taking Coumarin, but nine days pre-admission she had also taken Augmentin, an antibiotic with known hepatotoxic properties. Dr. Bassett acknowledged that this was a confounding factor, but warned medical practitioners who prescribed Coumarin to "observe patients closely for evidence of hepatotoxicity" (Med J Aust.163:106). Dr. Hunt suggested that Dr. Bassett’s patient only became hepatic after taking Augmentin (T.111), but I think that a closer reading of the article suggests that the patient was already unwell for six weeks or so before taking Augmentin.

3.12 On 11 August 1995, ADEC met again and considered data submitted by LAA, which included evidence of the efficacy of the drug. Following a consideration of the material, they resolved to advise the Minister that Coumarin tablets "appear to have a positive risk to benefit ratio in the treatment of post-surgical lymphoedema ... (and for another condition not relevant for these purposes)". They resolved that Lodema did not have efficacy for other conditions, which had been suggested by LAA. They also resolved to request the inclusion of a:-

"prominent warning statement in the Product Information on the potential for Coumarin to cause severe hepatic toxicity, which may be fatal, in accordance with the reports in the ADRAC data base".

 

3.13 ADEC also requested further data concerning pharmaceutical chemistry and quality control for Lodema. They resolved:-

"On the basis of efficacy and safety, that ADEC would not be opposed to the continued registration of Lodema tablets for the limited indications".

(Exhibit C.4a, p9).

Of course, one of those "limited indications" was post-surgical lymphoedema, the condition suffered by Mrs. Tzanavaras.

3.14 Following the August ADEC meeting, ADRAC published an article in the August edition of the Australian Adverse Drug Reactions Bulletin headed "Lodema and the Liver" (Exhibit C.9d). The article expressed "major concern" about the reports of severe injury, including one fatality, associated with Lodema. I was told by Dr. Hunt that this bulletin is distributed widely to the pharmaceutical industry and to medical practitioners who receive the Pharmaceuticals Benefit List (T.133).

3.15 It is to be noted that the ADRAC bulletin did not give any warning or suggestion as to how the drug should be used. In particular, it did not repeat the suggestion made by Dr. Casley-Smith in his April letter to the Medical Journal of Australia that:-

"liver function tests should be performed if the patient has symptoms suggesting hepatitis, and the drug should be withdrawn if the results are abnormal".

Dr. Hunt said that she had not seen that type of advice in the bulletin before (T.156). Dr. Harley said that he did not think that the evidence was clear enough, at that point in time, to have issued such a warning, particularly as it was thought at that time that any hepatotoxic reaction was reversible (T.91).

3.16 Another piece of information which became available in 1995 was the September 1995 edition of "Australian Doctor", a magazine in wide circulation among the medical profession (Exhibit C.11). That edition of the magazine repeated the information in Dr. Bassett’s July letter to the Medical Journal of Australia under the headline:-

"Watch for sign of liver problems. Patients prescribed Coumarin should be closely observed for signs of hepatotoxicity, Canberra doctors have warned".

 

3.17 Correspondence between Hamilton Laboratories, LAA and TGA continued for the rest of 1995 and into 1996, during which further negotiations were taking place concerning changes to the Product Information. Dr. Hunt said that LAA had provided another version of the Product Information which she still regarded as unsatisfactory, in the sense that it was not sufficiently strong, nor prominent, having regard to the requirements of the ADEC meeting in August. It is clear from the correspondence that the TGA were applying as much pressure as was possible on the LAA to have these issues resolved. Difficulties Dr. Casley-Smith was having in complying with requests for information, together with his illness during this period, caused delays in resolving these issues.

3.18 Following publication of the ADRAC bulletin in August 1995, further reports of hepatotoxicity began to arrive. Indeed, one study at Flinders Medical Centre in Adelaide showed a hepatotoxicity rate of 9/65, or nearly 14 percent, or 1,400/10,000, a vast increase on previous studies (T.115). The statistical validity of this report was questioned by Dr. Casley-Smith subsequently, and it was acknowledged by Dr. McEwen, the delegate of the Parliamentary Secretary to the Minister for Health and Family Services, in his letter dated 12 August 1996 (Exhibit C.4a, p128) that the incidence was more likely to be between .4 percent to .6 percent (40 to 60 per 10,000). This is still almost double the incidence previously calculated by the TGA (.37 percent).

3.19 By the time of the ADEC meeting in February 1996, the Product Information wording had been resolved, after considerable correspondence and some dispute with Dr. Casley-Smith. The document made it clear that the use of Lodema was limited to post-surgical lymphoedema and one other condition. A stronger warning about hepatotoxicity, including that life-threatening hepatitis may result from continuing therapy with Coumarin after abnormal liver function levels have been demonstrated, was also included (T.166). Importantly, though, these changes did not make their way into the MIMS Annual until the 1997 edition (entries for which must be lodged by the August of the previous year). So the relatively benign warning in the 1995 edition, which I mentioned earlier (i.e. that the condition was reversible on cessation of therapy), remained in MIMS until after Mrs. Tzanavaras’ death.

3.20 After ADRAC received Dr. Harley’s report about Mrs. Tzanavaras’ death, Dr. Hunt referred the matter to ADEC again, as this time there were no "confounding factors" such as Augmentin in the picture. ADEC met on 11-12 April 1996, and it was decided that the registration of the drug be reviewed. Dr. Hunt said that, as there was no "imminent risk to life" envisaged, the registration was not cancelled forthwith, but the sponsor (LAA) was given one month to justify its continued registration (T.120).

3.21 Dr. John Casley-Smith sought further information from the TGA to confirm that there were no confounding factors in Mrs. Tzanavaras’ case, and this was provided (see the correspondence in Exhibit C.9f). Indeed, Dr. Casley-Smith attempted to elicit information from the treating doctors at the Flinders Medical Centre, but was rebuffed by the doctors concerned. Mr. Blake’s evidence satisfies me that, in any event, Hamilton Laboratories had voluntarily ceased distribution of the drug after he was informed of Mrs. Tzanavaras’ death on 24 April 1996 (T.274).

3.22 The registration of Lodema by the TGA was formally cancelled on 12 August 1996 (see the letter of Dr. McEwen dated 11 August 1996, Exhibit C.4a, p127-129).

3.23 The LAA appealed against this decision, initially to the Minister, for reconsideration of the decision (Section 60(2) of the Therapeutic Goods Act), and then to the Administrative Appeals Tribunal (Section 60(8)), but both applications were unsuccessful. The drug has not been registered since that time.

4. Should Mr. Hoare have prescribed Lodema?

4.1 Ms. Redmond, counsel for the Tzanavaras family, submitted that Mr. Hoare erred in prescribing Lodema for Mrs. Tzanavaras on 26 September 1995 in view of the information available at that time, in particular the letters to the Medical Journal of Australia, the ADRAC bulletin and the article in the "Australian Doctor".

4.2 It is necessary to note that Mr. Hoare was, and is, a busy general surgeon in private practice, not a research scientist with specialised knowledge like Dr. Casley-Smith.

4.3 Mr. Hoare was a member of LAA. He had provided a copy of the 1994 newsletter (part of Exhibit C.10b) to Mrs. Tzanavaras’ then general practitioner, Dr. Rosenthal, in January 1995. This document also mentioned the fact that "very few patients" developed an "idiosyncratic hepatitis" which in all cases "disappeared when the drug was stopped". Having regard to Dr. Casley-Smith’s eminence in the field, I find that Mr. Hoare was entitled to rely upon his expertise, as well as the fact that the drug was registered by the TGA, when considering whether Lodema was a safe drug.

4.4 The evidence available to Mr. Hoare to the contrary of that proposition was (assuming he read each of these documents):-

• the Beinssen letter to Med.J.Aust. of December 1994 describing a reversible hepatotoxicity, and citing the rarity described by Cox et.al;

 

• the reply by Dr. Casley-Smith in Med.J.Aust. of April 1995 reviewing the literature to date, and supporting the figures of Cox et.al with results of his own research;

 

• the Bassett letter to Med.J.Aust. of July 1995 reporting a death, but with the possible confounding factor that the patient had taken Augmentin;

 

• the ADRAC bulletin in August 1995 expressing "major concern", particularly with relation to one fatal outcome, but repeating that the incidence of hepatotoxicity was of the order of 34/10,000;

 

• the article in the "Australian Doctor" repeating the terms of the Bassett letter;

 

• the entry in MIMS Annual, 1995 edition, describing any adverse reaction as "probably idiosyncratic" and "reversible";

 

Expecting Mr. Hoare to have read all of this information in the course of his busy practice would be the council of perfection. However, even if he had, he would have learned that any hepatotoxicity associated with use of Coumarin was considered idiosyncratic and reversible.

4.5 In light of that knowledge, the correct advice to Mrs. Tzanavaras was that she should cease the medication immediately if she began feeling ill, and seek medical advice. This is the advice that he gave to her (T.10). This is the same advice Dr. Harley would have given to his patients (T.48), and was the advice Dr. Thornes (one of the co-authors with Cox et.al in 1989) recommended to Dr. Casley-Smith in a letter to him in November 1994, and which advice Dr. Casley-Smith repeated in the draft "Consumer Product Information" he prepared around the same time (Exhibit C.9c). Dr. Harley confirmed that, if doctors had known at the time that even a small number of patients (even as low as one in 10,000) developed irreversible liver damage, "then I would certainly weight that very differently" (T.80). Unfortunately, that knowledge did not become clear until after Mrs. Tzanavaras’ death.

4.6 Mr. Hoare insisted that he would not have discussed possible side-effects in detail with Mrs. Tzanavaras when prescribing the drug, even if asked by her if the drug was "safe" as John Tzanavaras asserted that she did (T.11), since to do so was not his practice (T.206). He said that it was preferable to give a general warning of the type I have just mentioned rather than specifying in minute detail every possible eventuality. Since the general state of knowledge at the time was that any hepatic side-effects were reversible, I think that this was a reasonable stance.

4.7 Mr. Harley agreed, saying that there is a "fine line" between giving enough information and giving too much. If a doctor specifies some symptoms which the patient may expect, and not others, then there is a danger that the patient may only report the illness if the specified symptoms occur (T.78). He agreed with Mr. Hoare that a generalised warning, to cease the medication and seek medical advice if the patient becomes unwell, is preferable.

4.8 Mr. Hoare obviously took the view that Mrs. Tzanavaras was suffering from a severe and debilitating illness, and he wanted her to have the most efficacious treatment he could give her. He said:-

"I had to weigh up any risk here with the risk of her retaining that swollen arm and having it increase, the risk of getting to the point of amputation, the risk of developing an untreatable malignancy in the arm, against a 3 in a 1,000 risk, and a 3 in 10,000 mortality risk. It is not easy to evaluate that, but at the time I made that as a point in judgment and if I was wrong about that, then I have to bear that, but it was made, what decision I made was made in her best interests as I saw it at the time".

(T.206).

It is not my role to decide whether Mrs. Tzanavaras’ decision to take Lodema on Mr. Hoare’s advice was made with what has, since Rogers v Whitaker (1992) 67 ALJR 47, become widely known as "informed consent". To do so may be to enter territory forbidden to me by Section 26(3) of the Coroners Act 1975. However, from the point of view of whether Mr. Hoare should be criticised for prescribing Lodema, and the advice he gave Mrs. Tzanavaras in so doing, I do not consider that any such criticism is justified.

4.9 Ms. Redmond also criticised Mr. Hoare for failing to alert Dr. Sidhu of the need to monitor Mrs. Tzanavaras for signs of liver toxicity. Mr. Hoare responded, in effect, that to have offered such advice to a fellow practitioner, unsolicited, would have been presumptuous (T.191).

4.10 Although it could be argued that this is a rather old-fashioned attitude, it is not for me to dictate the courtesies shown between members of another profession. In any event, Mr. Hoare’s faith in Dr. Sidhu’s professionalism was well-founded because, when Mrs. Tzanavaras presented to Dr. Sidhu after becoming unwell, he performed the appropriate tests, then arranged for a referral to a specialist in Adelaide with what Dr. Harley described as "good speed" (T.40).

4.11 In all these circumstances, I see no ground for criticising Mr. Hoare in relation to his treatment of Mrs. Tzanavaras.

5. The role of the TGA

5.1 I have already outlined in considerable detail the way in which this complex series of events unfolded. Ms. Redmond criticised the TGA in her submissions on several grounds.

5.2 Section 4(1) of the Therapeutic Goods Act 1989 states:-

"The object of this Act is to promote the development of a national system for controls relating to the quality, safety, efficacy and timely availability of therapeutic goods used in Australia or exported from Australia, whether the goods are produced in Australia or elsewhere".

 

The TGA is charged with the responsibility for administering the system for these purposes.

5.3 Ms. Redmond argued that, while it is understandable that Coumarin, later Lodema, was "grandfathered" into registration, once the issues of efficacy and safety were raised, the TGA failed to ensure that these matters were established for the eighteen months or so until Mrs. Tzanavaras’ death.

5.4 I think that this criticism is unduly simplistic. The records produced by the TGA (Exhibit C.4a) demonstrate that they gave the LAA appropriate opportunities to be heard at all stages of the process, as indeed they are obliged to do by the rules of natural justice.

5.5 In doing so, the TGA were rigorous, to the extent that Dr. Casley-Smith was complaining that they were being over-zealous. In any event, there was no apparent urgency, at least until the Bassett letter in July 1995, and this provoked a strong and timely reaction at the ADEC meeting and in the ADRAC bulletin the following month. Again, this action was taken in the face of Dr. Casley-Smith’s objections, and since they came from such an eminent scientist, these objections could not be lightly brushed aside.

5.6 When it became necessary to substantially alter the Product Information in light of the Bassett letter, this process was commenced immediately by ADEC at the August 1995 meeting. Ms. Redmond criticised the fact that it was not finally achieved until February 1996, and so it did not enter the MIMS Annual until the 1997 volume. I do not accept that this was the fault of the TGA. They were dealing with Dr. Casley-Smith’s objections and granting him extensions of time in view of the fact that he was severely ill, indeed hospitalised with pneumonia. In those circumstances, the delays were not unreasonable.

5.7 Even after Mrs. Tzanavaras’ death was notified, the TGA decided not to act peremptorily, since it could not be established that an "imminent risk to life" was involved. They were of the opinion that they were obliged to give Dr. Casley-Smith and LAA further opportunities to be heard before deciding to cancel registration. They were obliged to be cautious and well-prepared, since their decision had enormous ramifications for sufferers of lymphoedema (Dr. Casley-Smith even suggested in submissions that patients were at risk of suicide if they were denied access to the drug - see Exhibit C.4a, p127), as well as for the LAA, Hamilton Laboratories and for them. As events subsequently demonstrated, the decision could also be challenged in the courts.

5.8 In all those circumstances, I find that the TGA acted with rigour and appropriate haste, and can find no grounds to criticise them.

6. The role of LAA and Hamilton Laboratories

6.1 Since this inquest was adjourned in July 1998, I have now heard evidence from Mr. Blake from Hamilton Laboratories and Dr. Judith Casley-Smith.

6.2 Without traversing the evidence in detail, it demonstrates that Doctors John and Judith Casley-Smith were dedicated medical researchers with a world-wide reputation for competence in the treatment of lymphoedema. They became convinced of the efficacy of Coumarin in the treatment of this painful and debilitating condition, a treatment which had been used for more than thirty years in Europe. Dr. Judith Casley-Smith pointed out that in Third World countries, where massage and other treatments are not feasible, it is the only practicable treatment (T.337).

6.3 At all times Dr. John and Dr. Judith Casley-Smith acted in what they thought were the best interests of the sufferers from the disease. LAA was a non-profit organisation which they sustained from their own resources for no financial benefit.

6.4 It has not been suggested that the Casley-Smiths acted in any way to mislead the TGA or any other person in relation to the properties of Coumarin. Nor is it suggested that they deliberately prevaricated, or did not do their best to satisfy TGA’s requirements for more information in appropriate form. They were under-resourced and Dr. John Casley-Smith became ill. This was unavoidable. Such delays as occurred in this case were unintended, and in any event not causative of Mrs. Tzanavaras’ death.

6.5 In the same way, Hamilton Laboratories also acted in good faith, relying on Dr. John Casley-Smith’s status as a world-renowned expert in the field in relation to the efficacy of the drug. The evidence of Mr. Blake satisfies me that they derived little financial benefit from so doing, and were attempting to support the Casley-Smiths in their efforts as local researchers of world-standing. Again, the evidence gives no ground for criticism of Hamilton Laboratories or its employees.

6.6 Indeed, it was not suggested by Ms. Redmond that any of these parties should be criticised.

7. Recommendations

7.1 Section 25(2) of the Coroners Act entitles me to add to my finding "any recommendation that might ... prevent or reduce the likelihood of a recurrence of an event similar to the event that was the subject of the inquest".

7.2 The most effective method of preventing a death similar to that of Mrs. Tzanavaras has already been adopted by the TGA and by Hamilton Laboratories, namely the cancellation of registration of the drug and withdrawal from distribution.

7.3 In April 1996, the TGA issued a "Medical Media Release", which no doubt alerted medical practitioners in Australia that the drug was considered dangerous (see Exhibit C.4a, p121A). There is also a notice in the current edition of MIMS that the drug has been deregistered.

7.4 It is true that Coumarin may still be obtained overseas, and via the Internet, and brought into Australia with a doctor’s prescription. In view of the warnings I have already mentioned, I think it would be unlikely that an Australian medical practitioner would issue such a prescription. If such a medical practitioner was so minded, I doubt that a further public warning would be likely to change his or her attitude.

7.5 In those circumstances, I do not consider that a further public warning is called for, so I will make no recommendation pursuant to Section 25(2) of the Coroners Act arising out of this matter.

 

 

 

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