(Aust Prescr 1996;19:3-6)
The Editorial Executive Committee welcomes letters, which should be less than 250 words. Before a decision to publish is made, letters which refer to a published article may be sent to the author for a response. Any letter may be sent to an expert for comment. Letters are usually published together with their responses or comments in the same issue. The Editorial Executive Committee screens out discourteous, inaccurate or libellous statements and sub-edits letters before publication. The Committee's decision on publication is final.
Editor, In reference to the editorial 'The price of urine' by Dr A. Dawson (Aust Prescr 1995;18:26-7), we agree that patient-relevant outcomes should be used to evaluate the efficacy and safety of all therapy-pharmaceutical and nonpharmaceutical. Improvements in symptoms and quality of life, significant adverse effects and impact on mortality would be appropriate measures.
Applying a comparative approach to surgery and finasteride in benign prostatic hypertrophy, the percentages of patients reporting symptom improvement in the two groups are similar.14 With regard to quality of life, compared with placebo, finasteride-treated patients were significantly less likely to report interference with function at work or regular activities, and waking at night due to symptoms; and significantly more likely to report improvement in worry and concern due to urinary problems.1,2 The companion article by Mr P. Stricker (Aust Prescr 1995;18:30-2) gave a review of significant adverse effects and the impact on mortality associated with surgery compared with finasteride.
Regarding alpha blockers, terazosin is available and has a similar cost to finasteride. Further, there are ongoing studies comparing finasteride with prazosin. Importantly, alpha blockers work differently from finasteride and have only been shown to be useful short term.5
Your editorial highlights a challenge for companies and the Pharmaceutical Benefits Advisory Committee, especially when introducing a pharmaceutical into an area with little data outcomes for existing therapy. In such cases, it is important to balance the desire for long term outcomes data which may take many years to collect against the needs of patients today.
Lee Ausburn
Director
Merck Sharp & Dohme Australia Pty Ltd
South Granville, N.S.W.
References
1. Gormley GJ, Stoner E, Bruskewitz RC, et al. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992;327:1185-91.
2. The Finasteride Study Group. Finasteride (MK906) in the treatment of benign prostatic hyperplasia. Prostate 1993;22:291-9.
3. Doll HA, Black NA, McPherson K, et al. Mortality, morbidity and complications following transurethral resection of the prostate for benign prostatic hyperplasia. J Urol 1992;147:1566-73.
4. Fowler FJ, Wennberg JE, Timothy RP, Barry MJ, Mulley AG,
Hanley D. Symptom status and quality of life following prostatectomy. JAMA 1988;259:3018-22.
5. Hytrin product information. MIMS Annual, 1994.
Dr A. Dawson, the author of the editorial, comments:
In my editorial I tried to emphasise the importance for practitioners of examining outcomes that are relevant to their patient's needs. To assess the relative benefits and risks of surgery versus medical treatment of benign prostatic hypertrophy requires a randomised controlled trial. The references quoted by Merck Sharp & Dohme are separate trials using different patient groups who may not have had comparable disease. While this presentation of data is a common marketing technique, the challenge for researchers is to compare alternative treatments directly.
In regard to the comparison of finasteride with placebo, the question for the practitioner is whether a statistically significant improvement in a symptom score demonstrated in a large trial is likely to be clinically significant to the individual patient and outweigh the known and unknown risks of drug treatment. The assumption that the long term outcome trials will be favourable for any treatment should be measured against previous experience using intermediate outcomes e.g. flecainide reduced ventricular ectopic beats, an intermediate outcome, but overall, increased mortality with long term treatment.1
Reference
1. Echt DS, Liebson PR, Mitch ell LB, Peters RW, Obias-Manno D, Barker AH, et al. Mortality and morbidity in patients receiving encainide, flecainide or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781-8.
Editor, Australian Prescriber has recently published two articles about DNA testing (Aust Prescr 1995;18:45-8 and 18:76-9). Another condition that can now be tested for is von Hippel-Lindau (VHL) syndrome.
The VHL Family Alliance provides information for families and physicians about the disorder. It can be contacted at the following address:
2/51 Musgrave Street YARRALUMLA ACT 2600 Telephone: (06) 285 1296 Fax: (06) 282 2037
Information is also available on the Internet by connecting to the VHLFA home page at URL then entering
http://kumchttp.mc.ukans.edu:80/instruction/medicine /genetics/vhl/vhlhomep.html
http://neurosurgery.mgh.harvard.edu:80/vhlfa.html
Jennifer Kingston
President VHL Family Alliance
Yarralumla, A.C.T.
Chloramphenicol for conjunctivitis
Editor, Writing as a patient, I wish to point out that in Dr J. Turnidge's editorial on antibiotics ('What to use instead of flucloxacillin' Aust Prescr 1995;18:54-6), he seems to approve of chloramphenicol drops and ointment for the eyes when he refers to its 'popular topical use'.
In another editorial1, the authors warn that chloramphenicol can suppress the bone marrow even when it is applied externally to the eyes. They recommend that it not be used unless there be no alternative and they suggest 'framycetin and fusidic acid are but two of many safer and equally effective preparations'.
John P. O'Brien
Pathologist
Randwick, N.S.W.
Reference
1. Doona M, Walsh JB. Use of chloramphenicol as topical eye medication: time to cry halt? Br Med J 1995;310:1217-8.
Associate Professor J. Turnidge, the author of the editorial, comments:
While mention was made in my paper of chloramphenicol being a popular topical treatment for superficial eye infections, there was no intention on my part to condone its routine use. As Dr O'Brien points out, cases of aplastic anaemia have certainly followed the use of topical eye preparations, and other topical agents can easily be substituted. Unfortunately, attempts to limit the availability of topical eye formulations of chloramphenicol by regulatory authorities in Australia in the past have not been successful. Indeed, the choice of topical antibacterials for ophthalmic use in Australia is quite limited. The choice of an alternative generates similar problems to that of finding substitutes for flucloxacillin. The ideal agent would be nonirritant, non allergenic and preferably not one used for systemic treatment. Many of the currently available agents do not fit the last category e.g. gentamicin, tobramycin, ciprofloxacin, tetracycline and chloramphenicol. Neomycin, framycetin and sulfacetamide are allergenic. Polymyxin B sulfate is not available alone and has poor grampositive cover. Only aminacrine and dibromopropamidine isethionate/propamidine isethionate (Brolene) minimise these problems, yet comparative experience with them is limited. Fusidic acid is not available in Australia for topical eye use. My personal preference is framycetin, but the time is right for development of new topical eye antibacterials using the above principles.
Attention deficit hyperactivity disorder
Editor, I believe that there is room for further comment on 'Stimulant treatment for attention deficit hyperactivity disorder' (Aust Prescr 1995;18:60-3) by Dr P. Hazell. I am concerned that his highlighted placebo effect of 35-40% will be taken as gospel.
It was mooted by Dr Russell Barkley in the late 1970s, but is not widely discussed by him lately. It has been mentioned once in the 1990s, but not by other researchers. If one medicates on the basis of pre testing, e.g. with a paired associate learning task, there is little if any room for placebo effect.
Dr Hazell's suggestion that 'drugs do not exert a direct effect on behaviour or learning problems' may be a quibble on the word 'direct'. The statement is in conflict with the article and references quoted by Christopher Gordon.1
Professor Adler's comments on 'an epidemic' are very emotive when Dr Paul Hutchins quoted N.S.W. figures which show that 0.8% of all children/adolescents are on neurostimulants. As with Dr Hazell, paired associate learning testing of the child's responses to medications precludes the need for 'single blind controlled trials' and obviates the need for cumbersome assessments of what works and what does not.
Michael J. Harris
Consultant Paediatrician
Sydney, N.S.W.
Reference
1. Gordon C. ADHD issues for special education. Aust J Special Education 1994;18(2):36-49.
Dr P. Hazell, the author of the article, comments:
Dr Harris has questioned the magnitude of placebo response quoted in my paper. One meta analysis1 has addressed this issue adequately, and found a placebo response rate of 30%. This is less than that reported in the narrative review of Barkley, but is still substantial. The question of which method is best for determining treatment efficacy in an individual patient is unresolved. While placebo trials have been recommended on theoretical grounds, there is a lack of evidence that these improve clinical management. I would welcome evidence from Dr Harris that supports the use of the paired associate learning task for the purpose of assessing the clinical response of ADHD children to stimulant treatment.
The important take home message for clinicians in relation to behaviour and learning is that clinicians, educators and parents should not expect conduct or learning problems to respond to stimulants in the absence of ADHD. Even in the presence of ADHD, the effect on learning averaged across 3 published meta analyses was 0.35 standard deviations, which is probably clinically non significant.1
Reference
1. Swanson JM, McBurnett K, Wigal T, et al. Effect of stimulant medication on children with attention deficit disorder: a 'review of reviews'. Exceptional Children 1993;60:154-62.
Editor, The review by Dr G. Vaughan ('The Australian drug regulatory system' Aust Prescr 1995;18:69-71) shows the improvements that have occurred. The Therapeutic Goods Administration, the Australian Drug Evaluation Committee and all associated are to be congratulated. Physicians reading the review might be misled by the evaluation times for new chemical entities quoted. I believe these refer strictly to evaluation rather than the overall time it takes as the clock is stopped once the Therapeutic Goods Administration has asked questions of the company. For example, the latest Industry survey shows an average time of 373 working days (i.e. 522 actual days) for the delegate's decision rather than the 190 days shown in the review. This is regrettable and there is more than one reason for it. However, the bottom line for prescribing physicians is that they need to know how long it takes for drugs to be approved, so overall times will be more relevant to them.
Jeff Adams
Biotechnology Development Manager
Janssen Cilag Pty Ltd
Lane Cove, N.S.W.
Dr G. Vaughan, the author of the article, comments:
Thank you for giving me the opportunity to respond to the letter from Dr Adams about my article. The people and groups involved with drug regulation will appreciate the congratulations given by him.
It is true the evaluation times do refer to the time taken by the Therapeutic Goods Administration (TGA) to carry out its evaluation role. There can be a need, depending on the quality of the application, to seek further information from the applicant company. Naturally the TGA cannot be held responsible for the considerable time taken by companies to respond to some requests.
As indicated above, the need to ask questions is very much related to the quality of the application. If any sponsor believes that the questions are unreasonable, then they can appeal through a Standing Arbitration Committee or the formal appeal processes which were introduced following the Baume report.
The reason why the TGA refers to evaluation time in working days is because the Baume report set standards using this terminology, which was eventually included in the legislation related to evaluation timelines.
Editor, Dr H. Newman ('Letters' Aust Prescr 1995;18:57) states that for many years he has stressed to his trainees that 16 gauge or larger intravenous cannulae need not be used for resuscitation because the flow of a watery solution through an 18 gauge is 'only a little slower'.
It would seem that his trainees, with their intimate knowledge of Poiseuille's law (laminar flow rate alpha radius4), have been too polite to point out that a 16 gauge cannula (ID 1.30 mm 'Surflo') can in fact achieve a flow rate 3.5 times greater than that of an 18 gauge (ID 0.95 mm). Dr Newman's ability to compensate by raising the flask appears to defy Galileo's theory (velocity alpha square root height).
I suggest we observe the resuscitation protocol endorsed by the 5 learned Colleges, for the physics as well as the therapeutics!
Phillip Gray
General Practitioner
Queanbeyan, N.S.W.
Cost as a factor in drug registration
Editor, The article by Dr G. Vaughan (Aust Prescr 1995;18:69-71) on the Australian drug regulatory system was informative and mentioned common pressures on the regulatory authorities such as the limits on the time to evaluate a drug. In Australia, the cost of the drug is not considered during registration. If this article is not read with the article by Dr D. Graham on the Pharmaceutical Benefits Scheme (Aust Prescr 1995;18:42-4), it may give the impression that the process before the drug reaches the patient does not include a consideration of the cost. This is not true, as cost effectiveness is evaluated before the drug is included in the Pharmaceutical Benefits Scheme. This pattern is almost universal in the developed world; the drug is registered and then negotiations occur between the pharmaceutical company and the buyer (departments of health, state sponsored/regulated insurance schemes, etc.).
In developing countries, there are important differences which have serious implications for the cost of pharmaceuticals. Applications for registration of drugs are generally considered on the criteria of efficacy, safety and quality. If a drug is approved, it reaches the patient with no negotiation on price; the pharmaceutical company charges whatever price the market in the private sector will bear. In the developing countries of the Asia Pacific region, the private sector is substantial and provides from 40-95% of health care and the health insurance schemes are rudimentary, the patient directly bears the full cost of the drug. This can lead to enormous differences in price; in Sri Lanka, the difference in price between a generic and a branded diazepam is 10 000%. When we have tried to include cost in the registration process, we are told this is not part of the registration process in other countries.
Articles on the registration of drugs in the developed world should therefore highlight the important fact that prices of drugs are tightly controlled. This would be useful to the countries in the developing world trying to regulate prices.
K. Weerasuriya
Professor of Pharmacology, University of Colombo, and
Secretary, Drug Evaluation Subcommittee
Ministry of Health
Sri Lanka
