Dr Marshall
267 In his affidavit of 30 July 2009 Dr Marshall said that he had been asked by the solicitors for Alphapharm to outline his knowledge and understanding of the state of knowledge of those working in the field of drug formulation as at 25 March 1996 and that he had tried to put himself back in the position he was in as at that date for this purpose. According to Dr Marshall the field of drug formulation was "well developed" in Australia by this date. In response to the general instruction identified, Dr Marshall said that in "order to propose a considered formulation there are a number of standard steps, with which I was very familiar as a formulator prior to 25 March 1996".
268 The "very first step" Dr Marshall identified was to conduct a search of the available literature and other information on the drug. The next steps would be to review the material, investigate development pharmaceutics, review any applicable patents, conduct pre-formulation studies and prepare a proposal of prototype formulations and processes. Dr Marshall then identified a series of factors that a formulator must consider in "formulating a commercial pharmaceutical dosage form".
269 Dr Marshall was also asked by the solicitors for Alphapharm to outline his knowledge and understanding of "the state of knowledge of ER formulation among those working in the field of drug formulation in Australia as at 25 March 1996 including the motivation for developing an ER formulation of a particular compound as at 25 March 1996". Having identified those matters and the "general underlying rationale and principles used in the more common ER (solid dose) diffusion and dissolution controlled systems", Dr Marshall concluded that in March 1996 he:
… would have considered that in the absence of any information to the contrary, ER formulations of any drug using well known formulation techniques and excipients… would be potentially feasible.
270 In his affidavit of 10 August 2009 Dr Marshall said that he had been instructed that the proceeding related to a product developed by Alphapharm known as Enlafax which contains the active ingredient venlafaxine hydrochloride. Further, that on 7 May 2009 (that is, before preparing his affidavit of 30 July 2009) Alphapharm's solicitors had provided him with a copy of the formulation details for three different strengths of Enlafax, as well as a description of hydrogel tablet technology (in fact, the description from the patent itself which refers to extended release drug formulations being conventionally produced as drug formulations as compressed tablets by hydrogel tablet technology). Dr Marshall was asked to consider whether the Enlafax formulations fell within the description. Thereafter, on 8 August 2009, Dr Marshall was provided with a copy of the patent. However, before being provided with the patent Dr Marshall said in an affidavit of 24 December 2009 that he had provided a report (exhibit PAM-11), being his principal evidence in the proceeding.
271 According to this report, Dr Marshall was asked to explain the steps he would have taken in 1996 "to formulate an ER venlafaxine hydrochloride pharmaceutical" and that he had done so in the report. Dr Marshall said that during his employment at Faulding he was often given a brief which identified a drug of interest and directed research and development investigations which were "usually focussed on reformulation of the drug of interest, eg as an ER formulation or as an alternative IR formulation" so that, consequently, he was involved in "many reformulation projects during [his] time at Faulding as a formulator". As disclosed in paragraph 32 of the report Dr Marshall was instructed to state:
…having regard only to the information contained in the Martindale Monograph, the Morton Article and the [First Troy] Article… what steps I would have taken before March 1996 to develop an ER formulation of venlafaxine hydrochloride.
272 In the report Dr Marshall then said that he would "as a matter of course" have referred to the Martindale Monograph as "it is a standard reference book that I have kept close to hand - usually in my office - throughout my career as a formulator". Both the Morton and Troy articles are referred to in the Martindale Monograph.
273 Having reviewed this information Dr Marshall said he would have a "high degree of confidence that [he] would succeed in creating an ER formulation of venlafaxine hydrochloride".
274 In the affidavit of 24 December 2009 Dr Marshall also said he had now been asked what steps he would have taken before 25 March 1996 to develop an ER formulation of venlafaxine hydrochloride "if the Martindale Monograph was not available... before 25 March 1996". Dr Marshall's affidavit does not explain why he was being asked to undertake this exercise. According to Dr Marshall, by the "extensive literature search" that he would have undertaken in any event, he would have found other articles available as at 25 March 1996 that would have provided him with the same information which he extracted from the Martindale Monograph, namely:
(a) that venlafaxine hydrochloride has a number of adverse events, or side effects, and that it is reported that the most frequently reported adverse events are nausea, headache, insomnia, somnolence, dry mouth, dizziness, constipation, asthenia, sweating and nervousness;
(b) other extreme adverse events reported included convulsions;
(c) that venlafaxine should be used with caution in patients with hepatic or renal impairment and those with a history of myocardial infarction or unstable heart disease;
(d) that venlafaxine should reportedly not be used concomitantly with monoamine oxidase inhibitors (MAOIs);
(e) the absorption, distribution, metabolism and excretion properties of venlafaxine hydrochloride;
(f) that venlafaxine is well absorbed from the gastro-intestinal tract and undergoes extensive first pass metabolism in the liver, mainly to its active metabolite O-desmethyl venlafaxine ("ODV");
(g) venlafaxine's major metabolite ODV is active;
(h) protein binding of venlafaxine and O-desmethyl venlafaxine is low;
(i) that steady-state plasma concentrations are reached within about 3 days;
(j) the climination half life reported for venlafaxine is 5 hours and for O-desmethyl venlafaxine is 11 hours;
(k) that venlafaxine hydrochloride is excreted through the kidneys;
(l) that venlafaxine is given orally in an initial daily dose of 75 mg that is given in two to three divided doses with food and which may be increased to 150 mg daily if necessary to a maximum daily dose of 375 mg;
(m) that patients with renal or hepatic failure are to be given reduced doses, with the suggested dose in these circumstances being half of the usual dose and only administered once daily; and
(n) that the dose may also be increased to 150 mg in patients who do not have renal or hepatic failure.
275 In Dr Marshall's words:
38 I have identified all of the above information in one or more of the articles listed in paragraph 27 above. In addition, I note that other information useful to me as a formulator, obtained from the articles discussed above, includes:
(a) that the metabolite ODV contributes to the overall antidepressant effect of venlafaxine. This teaches me that first pass metabolism is not necessarily a problem.
(b) that the venlafaxine and ODV molecules have an asymmetric carbon atom and it appears that both enantiomers of venlafaxine and ODV are biologically active.
39 Consequently, I would have had the same information available to me regardless of whether I had access to the Martindale Monograph or not. The information I would have needed is, and was prior to 25 March 1996, readily available by conducting a routine literature search.
276 By the hearing it was common ground that, in the editions available at 25 March 1996, neither the Martindale Monograph nor the Merck Index would have contained any information about venlafaxine hydrochloride. The unavailability of information from the Martindale Monograph is the reason why Dr Marshall was instructed to identify the steps he would have taken to develop an ER formulation of venlafaxine hydrochloride "if the Martindale Monograph was not available...before 25 March 1996". Dr Marshall knew that the Martindale Monograph was not available by the time he prepared the affidavit of 24 December 2009 but, as apparent from his reference to the Merck Index discussed below, did not then know that the Merck Index also was unavailable.
277 Other matters emerged during cross-examination.
278 First, although not tendered as part of his affidavit of 24 December 2009, Dr Marshall in fact said that if the Martindale Monograph was not available at 25 March 1996 he would have referred to the Merck Index as discussed in paragraphs 5 to 7 of his report. These paragraphs also were not tendered as part of the report but were the subject of cross-examination. According to these paragraphs, if the Martindale Monograph was not available, the first thing Dr Marshall would have done "when asked to develop an ER formulation of venlafaxine is to go to a reference such as the Merck Index". Dr Marshall attached to his report an extract about venlafaxine from the 12th (1996) edition of the Merck Index saying:
This is a text that I had on the shelves in my office and is a standard point of reference for chemists generally.
279 The following exchange occurred during cross-examination:
That sentence:
This is a text that I had on the shelves of my office and is a standard point of reference for chemists generally.
was language employed by you with the intention of conveying graphically. You would have consulted that very work on your shelves as the first point of reference, do you agree? It was a it is a very good text, it is a very good point of reference. So if the information is there, then it is a good place to start.
But the language you employed was intended to convey graphically that, in effect, you'd swivel around in your chair and reach for the Merck Index in this case, that
was the intention you had in including that sentence, wasn't it? Well, I would have accessed that article, that document, if I'd had it.
You know, don't you, that if you'd swivelled around in your chair on or prior to 25 March 1996 and reached for the Merck 1996 publication there would have been a blank space? I actually don't know that because the beginning of the Merck Index says 1996.
Is this the position: aren't you aware of the fact that the Merck Index wasn't published for 1996 as at 25 March 1996? Not at the time I wrote that report.
Well, you know that now, don't you? As of yesterday.
280 In other words, Dr Marshall's evidence, properly understood, is that had he been asked to develop an ER formulation of venlafaxine hydrochloride the first thing he would have done is refer to the Martindale Monograph and the Merck Index. He in fact reviewed those texts and found out information about venlafaxine hydrochloride as well as references to other articles, such as the Morton and First Troy articles, which he also reviewed. Having collated that information into a series of convenient propositions, Dr Marshall then undertook a literature search and found articles supporting those propositions.
281 However, had he in fact been undertaking the exercise as at 25 March 1996, Dr Marshall would not have found any information about venlafaxine hydrochloride in either the Martindale Monograph or the Merck Index. He would not have had the references to other articles provided by those texts. He would not have had the series of propositions he collated from those texts as a foundation for his other literature searches.
282 Second, Dr Marshall was asked about his experience at Faulding (about which he gave evidence in his affidavits identified above). The following evidence emerged:
You have a recollection, don't you, a clear recollection, in doing your formulation activities at Faulding of relying on Merck? Yes.
… Did any of that work include reformulating an existing immediate release product for extended release? Yes, it did.
Is that a number of occasions which you can count on one hand or identify? Well, there were a vast well, not a vast, but there was a quite a number of drugs that
were worked on and some reached fruition, some didn't.
I'm just trying to can we just concentrate on it being on or prior to 25 March 1996 firstly, secondly during your time at Faulding and, thirdly, work which you were personally engaged in, okay? Mm.
How many occasions, are you able to say, did you get involved in work which involved reformulating an existing immediate release drug into either a possible or potential extended release formulation? If we expand the consideration to controlled release, which includes delayed release, then it would be probably 20 to 25 of that number. If we're just talking about extended release, then it would probably be three to five, something like that.
To be clear, that distinction, by delayed release, you are referring to formulation by example of using enteric coding? As an example, yes.
…
Did I understand you correctly to say that of the three to five extended release which you were looking at, that, what, not all of them came to fruition? No, for different reasons, commercial reasons. I remember one, it stopped and started several times.
So commercial reasons was one reason for some of them. You said for different reasons? Others the other projects took priority. At any one time you could be working on a number of different drugs and the priorities could change.
So where priorities change, do I understand you to be indicating that the work just never got completed? Yes.
And at the date at which the priority changed, the work which caused attention to be directed away from that project had not, obviously, been successfully completed? I'm not quite sure I understand your question.
All right. Perhaps I will start again. Of the three to five which you referred to, can you identify any of them, and if so which, which resulted in a drug which came to market? I can't remember because many of them were still in progress when I left R&D.
Of the three to five? Yes. When I left R&D, I don't think any of those three to five had reached market.
And you don't know whether any of them did; is that right? Not since, no. I left Faulding in 1990 and I haven't kept track.
Is this the position: confining ourselves to simply extended release formulations, none of the ones you were involved in actually reached market? I can't say one way or the other, whether they reached market or not, but they didn't reach market while I was on the project.
I'm sorry. Yes, thank you. Prior to Faulding, am I right in thinking that you weren't involved in extended release formulation work? No, I was not.
And between leaving Faulding in 1991 and 25 March 1996, were you involved in extended release formulation work? On an advisory capacity.
But not in an actual formulating capacity? In an advisory capacity for formulation but not hands on.
How many extended release formulations did you give advice on in that 91 to 25 March '96 time period? I think it would be about the same number, maybe two or three, perhaps.
Can you identify the names of those products? No, I can't.
Is that because you don't remember them or there is a confidential concern? Confidentiality.
But you remember them? No, either way.
Well, there is not going to be a confidentiality concern if you don't remember them, is there. You don't remember them, that is the position, is it? Not exactly, no.
283 Dr Marshall agreed that:
Do you agree with me that you haven't set out anywhere in your affidavits, eight of them, the fact that, to the best of your recollection, you have only ever been involved in formulating somewhere between three and five extended release formulations from immediate release to extended release, none of which you can say were successful and none of which you can say were for single daily dosage, do you agree you have not said that anywhere in your eight affidavits? I haven't said that specifically, no.
284 Third, as to the significance of the Merck Index and Martindale Monograph to his experience in working on ER formulations Dr Marshall gave the following evidence:
Is it fair to say, accepting the difficulties of memory, to which you have directed the court's attention, that you don't have a recollection of ever doing any work on an extended release formulation without having reference to the Merck Index; correct? I wouldn't draw that analogy. The Merck Index was one of others.
I'm not asking. I'm just asking you whether you have a recollection, I am not having an argument with you. You're the witness, okay. You have got a recollection or you don't? Well, I can seem to recall using the Merck Index on many occasions.
All right. But I am asking I put this question to you: do you agree with me that you can't recall a single occasion at Faulding in which you undertook work on an extended release formulation without the benefit of the Merck Index, that is, information about the drug in the Merck Index, can you? I guess if you put it specifically like that, then no.
I suggest to you all the searches which you say you would have undertaken back on 25 March 1996 in relation to consideration of an extended release formulation are all searches which you say is based on your prior experience; is that right? Yes.
But your prior experience, as far as you can recall it, doesn't extend to a situation where you didn't have as a starting point the Merck Index, do you agree? Well, I worked on quite a number of different formulations and very frequently I would call upon the Merck Index. I worked on quite a number of different formulations besides extended release.
…
In other words, to the extent Faulding got involved in this formulation exercise, it was in relation and to the extent you were involved, it was in relation to drugs which had been on the were known on the market as being quite successful; correct? Well, they were known on the market. They were approved chemical entities, they weren't new chemical entities.
None of them involved drugs which had yet to be sold on the Australian market, did they, to the best of your recollection? To this, my recollection, most, if not all, would have already been on the market somewhere, perhaps not necessarily Australia, but somewhere.
But your knowledge of them was derived in each case from knowledge that they were on the market? Well, the knowledge would have been drawn from a variety of sources.
What I want to suggest to you: in each case in which you did work in relation to reformulation of one of these drugs in relation to extended release, to the best of your recollection, you had access not only to Merck but to Martindale for information and it contained information about the particular drug; do you agree? Usually. Not always but usually.
Again, you don't recall an instance when you were working on a drug which didn't have information in Martindale, do you? Well, I can't recall every single time I looked up the Merck Index or every time I looked up Martindale, but what I can say is they were both reference texts to which I and my colleagues often referred to.
What I want to suggest to you, Dr Marshall, is to the extent you have talked about searches you would have done back in 1996, if you removed from your available information Merck and Martindale, I would suggest to you this is a whole new world which you had never experienced? No, that is not the case.
The idea of doing searches without the benefit of Merck and Martindale and saying what you would have done, you're talking about a hypothetical situation which you actually never experienced; that is right, isn't it? No, that is not correct.
You can't identify a single extended release formulation where you undertook
searches without the benefit of the starting point of Merck and Martindale, can you? I didn't do every search based you know, using Merck or Martindale as a starting point.
…
Do you disagree with the proposition that in this report you were intending to indicate that you would have relied on the information you identified in Martindale? Well, I would have used the information from Martindale as a starting point. But it is a similar situation with the Merck Index. If you haven't got it or if that particular drug is not in there, then you have to get that information from somewhere else.
…
I'll put this proposition to you again: would you agree with me that you're intending to indicate in this report that you would have relied on the information which you say you would have found in Martindale 1996? Yes, if the monograph was available in the Martindale, I would have used it not only for the information that it provided but also it provides leading references and also source references, because remember it is the summary document.
And nowhere in those paragraphs, or anywhere else in that report, do you add the qualifier "if it was available", do you? The assumption is it would have been available, that is true.
Nowhere in those paragraphs do you indicate the qualification "if it was available", do you? Not within those specific paragraphs, no.
You were positively intending to indicate to any reader of the report that in fact it was available, weren't you? Well, the report was written on the assumption the monograph was available and it was an acceptable source of information at that time.
285 Dr Marshall agreed that he had not disclosed in his affidavit of 24 December 2009 that he was by then aware that the Martindale Monograph was not an available source of information about venlafaxine hydrochloride as at 25 March 1996.
286 When asked about the process he undertook in terms of literature searches, Dr Marshall gave this evidence:
Would you agree that you found Martindale to neatly encapsulate a number of pieces of information which you identify in paragraphs 8 and following? Yes, it provides a nice summary in addition to the source references.
When you, in a later affidavit, said you have managed to find each of those references in other material, of course that is not the process you would have undertaken back on 25 March 1996 if Martindale had not been there? Well, yes, it would have been. If I didn't have Martindale, I would have done a literature search by another means.
The process which you reported in this report was to identify some pieces of information encapsulated firstly in Merck, and then secondly in Martindale, and then later, having encapsulated and digested those propositions, you went looking over a series of disparate and different publications for those individual pieces of information. Isn't that the process that you actually undertook? I got some leading references from Martindale and from Merck which I obtained. I was then advised what would I do if I didn't have Martindale, and I undertook a more extensive literature search using standard databases which I would have done in any case because you don't always get everything you want out of two texts.
What I'm suggesting is the process you undertook was to firstly identify these propositions out of Merck and Martindale and then subsequently went looking for the same propositions which had been neatly encapsulated in those two texts amongst a raft of other literature? Or, as I said, the standard approach is to get as much information as I can.
Subject to that you agree? Though Martindale was a good starting point.
So you agree with me? Well, I I'm just restating what I did.
But you agree that as it turned out, the way you did it, was to list the pieces of information which you found from Merck and Martindale and then thereafter go and look for them in the literature separately? Well, thereafter I looked for additional information because Martindale and Merck weren't exhaustive.
…
What I suggest to you is you report that you went and found the information which you had previously distilled in other disparate publications, do you agree with that? Yes, I found the same documents independently.
287 Fourth, Dr Marshall did not have a record of all communications from his instructing solicitors or others regarding the proceeding. Dr Marshall agreed that from the time he was engaged by the solicitors for Alphapharm sometime in May 2009 (that is before he prepared his principal evidence), he appreciated that the case related to a patent owned by Wyeth and he also assumed that Alphapharm was "seeking to market a similar compound and that Wyeth had the drug out in the market". From his affidavit of 10 August 2009 Dr Marshall knew that he was retained on behalf of Alphapharm relating to its Enlafax product - being an ER formulation of venlafaxine hydrochloride. Further, as his affidavit of 10 August 2009 also disclosed, he was aware that the matter related to a patent dispute. He was also aware that the priority date (a term the significance of which he understood) was 25 March 1996. From this it must be inferred that Dr Marshall was aware that, as at 25 March 1996, an extended release formulation of venlafaxine hydrochloride had been developed.
288 In other words, when expressing his primary opinion that as at the priority date he believed he could successfully produce a once-a-day formulation of venlafaxine hydrochloride, Dr Marshall had information available causing him to assume that at least two successful ER formulations of that compound had been achieved, one in 1996 and Alphapharm's product more recently. The following extracts from the transcript confirm this to be so:
The circumstances in which you express your report of 8 September 8 August 2009, which is PAM 11, and opine as to whether or not you thought you could successfully produce a once a day formulation, extended release of venlafaxine hydrochloride,
the first time you express that opinion and as to what you would do, is after, is it not, you have studied what you assume to be a formulation, namely Enlafax, which identified a particular way of doing it and which you assumed was successful; correct? Yes.
And in circumstances where you assumed that Wyeth had also produced a successful once a day formulation. That is right, isn't it? Well, of course, I had no idea what the Wyeth formulation was.
So having those two propositions firmly in your head, you then purport to express an opinion as to what you say you would have done and that you think you could have done successfully; correct? That is the chronology, isn't it? I'm not sure it is. I thought I provided the report before I saw the patent. So I'm confused.
Whether you provide the report before you saw the patent you'd certainly seen the Enlafax formulation? Perhaps I am confused. I'd seen the Enlafax formulation.
And formed the view that somebody had successfully made a once a day formulation of venlafaxine hydrochloride. That is right, isn't it? Again I come back to the question that was asked of me how would I do it, and I would do it by using spheronisation.
You were asked the question whether you think you'd be likely to be able to do it, that was effectively the question you were asked? Yes.
Yes. And you answered that after you'd studied and formed the view that somebody had already done it twice, possibly two different ways; is that right? Possibly.
…
How do you suggest you could put yourself in the position you were in on 25 March 1996, having never dealt with venlafaxine hydrochloride and having never actually seen to completion any once a day formulation of any compound, how do you suggest you could give a sensible unfiltered opinion of the likelihood of success in circumstances where you'd already studied this Enlafax formulation or what you assumed to be? You can't, can you? I can only do to the best of my ability of putting myself in that position.
Was there any reason why, in your report, if you look back at 7 91, why it is that you didn't say in the report, listen, I should disclose this: I have studied an Enlafax formulation or what I have been told it is and I have drawn the assumption they have successively made it in the way they did and it is therapeuticically effective, and I have made the further assumption that Wyeth has done the same thing. Why didn't you say that, that would have been a relevant thing to put out in this report, wouldn't
it? Perhaps I should have.
Should have. Is that what you answer, you should have? I can't really explain.
289 Other parts of Dr Marshall's evidence show the extent of his awareness that by the priority date venlafaxine hydrochloride had been successfully developed in an ER formulation. In respect of the material he received in May 2009, Dr Marshall gave this evidence:
In other words, you understood, on receipt of these documents, that you're being asked to comment on a formulation which had been approved by the TGA, or at least an application had been put in by the TGA? Yes, I did.
By Alphapharm? Well, Alphapharm is noted as the sponsor.
And you understood from that that this was being represented to the TGA as a single daily dosage form of venlafaxine hydrochloride for treatment in depression? Well, I assumed that from the contents on this page.
And that it had been successfully formulated; correct? Well, I wasn't sure of the status of approval. A note had been submitted, but I wasn't sure whether it had actually been approved by TGA.
But your assumption was it had been successfully formulated? The assumption was if it had been submitted, then it would have been successfully formulated, otherwise you wouldn't submit.
Exactly. Your assumption also was that there was support for its therapeutic effectiveness? That depends on the nature of the submission.
You knew Alphapharm to be a generic manufacturer so described? Yes, I know Alphapharm are a generic manufacturer.
And at the time you saw this material, you knew Wyeth was the other party to the proceedings? I think so.
And you know that Wyeth is known by the it falls within the category of innovator company? Yes.
And you knew that the proceedings involved a patent for that Wyeth held in Wyeth's name? Well, I understood that there was a dispute between Wyeth and Alphapharm.
And you understood from your general experience that generics such as Alphapharm will often seek approval for the same drug relying on, indirectly, the approval for the innovator drug? That depends on the nature of the submission.
But that is often the case, isn't it? It's certainly the case for immediate release, which are relatively straightforward, but not necessarily for others. Not necessarily for all dosage forms either.
But you assumed, didn't you, that Wyeth had its own XR drug? I think I assumed that, yes.
In other words, another single daily dosage formulation of venlafaxine hydrochloride, that was your assumption? That is my assumption.
If you can then go back to again, your assumption was that had been successfully formulated by Wyeth? Well, again, because if that had been on the marketplace, it had been approved by the appropriate agency, therefore one assumes it is successful.
290 Fifth, when asked about clinical efficacy, Dr Marshall said that was not relevant as at 25 March 1996 "from a formulator's perspective". When asked about the way he approached his report in light of this answer the following exchange occurred:
Do you deal with this on the basis that somebody has told you to do it, not whether you should consider whether you should do it or not? Is that the way you approached your report? Pretty much.
So decisions as to whether or not it would work or wouldn't work, or whether it was a good idea or a bad idea, that had been made higher up the line so far as you were concerned? Essentially.
And to the extent any statement by you in all your affidavits might be read otherwise, they should be understood in the light of the last answer you just gave; correct? They should be understood in the light of how would you go about formulating an ER of this particular drug.
Once told you should do it? Yes, once told it was worthy of or, not even it was worthy, but
You were told to do it? Yes.
That is right, isn't it? That is how you have approached ? The instructions were: how would you go about formulating under different circumstances?
But the approach you have fundamentally taken, notwithstanding there may be references to some other considerations in your reports, is you approached it on the basis it wasn't your decision as to whether to do it or not, you were just being told as a formulator to do it and you were just responding to the proposition, well, do you think I could I have done it? Yes, how would I do it.
Is that right? Yes.
And hence, just to complete this, if one looks at [the Morton article], and there is a heading Controversial Issues perhaps I won't ask you to read it but to the extent there are words in there which might suggest the jury is still out as to whether venlafaxine actually offers any benefit over any other drug, that is not a matter which you were concerned to be considering for the purposes of the work you did in this
report? No, whether it was superior to another drug or not wouldn't have been my concern.
291 In other words, Dr Marshall's starting point was that he had been instructed to prepare an ER formulation of venlafaxine hydrochloride irrespective of whether such a formulation would be "worthy" or offered any benefit over any other drug.