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	The XXX stories of the year 2002: about a footballer’s intimate dimensions and a human side to Brazilian prisons

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	It is about patents and market opportunities indeed, not patients

Top The XXX stories of... It is about patents... Generics again... The French approach to... Good quality information for... Nobel prizes: is it... Perhaps not everyone knows... References

 
In December we gave you news about ciprofloxacin and anthrax, and the pressures placed by the US government and, we later learned, the Canadian government on Bayer. Bayer was seeing a huge increase in public demand for its agent, and accepted calls to sell its drug at a further discount to the government (99 cents per pill ), compared with the usual bulk order discount (US$1.77 per pill). In doing this it did not risk the loss of its patent. One just wonders how, from now on, the US and Canadian governments will defend their drug companies when Brazil and South Africa, which face an AIDS epidemic and are certainly not as rich as the North American governments, decide to ‘infringe’ the patent rights of companies which refuse to lower the cost of the drugs they sell (see Annals News, April–June 2001).

At the same time the giant Johnson and Johnson, according to Le Temps, October 30, had proposed to sell its own drug called Levaquin to the US government at a low price ...but there was a ‘small’ condition, apparently: the Food and Drug Administration should have added anthrax to the label of the agent... and Pfizer announced that as the particular strain of anthrax was also doxycyclin sensitive, it would increase the production of this antibiotic. The only vaccine which is under production is the one of BioPort, which is under exclusive contract with the US military. Bioterrorism is seen as an investment opportunity by the stock market. Some small companies with innovative technologies for vaccine production or detection have seen their NASDAQ value increase substantially (Avent, +57%; and Nanogen, +49%). We, of course, hope that their value will drop soon...

	Generics again...

Top The XXX stories of... It is about patents... Generics again... The French approach to... Good quality information for... Nobel prizes: is it... Perhaps not everyone knows... References

 
An excellent press release of the University of Michigan allows us to continue the debate over substituting one drug product for another. This of course isn’t new—by some accounts, it goes back at least 100 years, but it has intensified in recent years with drug companies, insurers and health care providers (including governments in many countries) at odds over rising pharmaceutical costs. A group of University of Michigan researchers conducted an in-depth look at the issues of brand-name medications versus their generic equivalents, and they are publishing their findings in a seven-article series in the Journal of the American Pharmaceutical Association (http://www.aphanet.org/JAPhA/japha.html)"We feel there’s a lack of knowledge on the part of employers, insurers and providers regarding generic drugs, and that these changes in prescription drug benefit programs should be made based upon a better understanding of the issues," said Duane Kirking, lead investigator on the project, of the motivation for the team’s research. The Blue Cross Blue Shield of Michigan Foundation provided US$50 000 in funding toward the research.

Among their findings:

In spite of changes in the marketplace and projections for massive growth, generic drugs appear to have stabilized at approximately 40% of prescriptions and 10% of pharma-ceutical sales. Kirking said he doesn’t expect that share to change substantially, because even as manufacturers bring more generics to market, brand-name manufacturers introduce more new (and often more effect-ive) drugs, which enjoy patent protection before they have to face competition from generics.

The science demonstrating that generics are, in fact, bioequivalent to the name brands with which they compete has improved greatly. One argument opposing generics has traditionally been that they are not a true substitute, but now it is easier to tell if that is true scientifically, Kirking said.

Significant restructuring in the pharmaceutical industry has led to cases where the same company makes a brand-name drug and its generic equivalent, or owns a subsidiary that does, while those companies that make only generics are merging and consolidating.

Kirking, who is Professor and Chair of the Department of Social and Administrative Sciences in U-M’s College of Pharmacy and a research scientist in health management and policy at the U-M School of Public Health, said many people in the health care industries looked to generics as a quick-fix way to cut costs. For a number of reasons, that is not realistic, he said.

For example, a number of the most expensive medications are still under patent so no generics exist, and once the end of the patent draws near, clever pharmaceutical manufacturers reformulate—such as providing a 12-hour pill instead of one that works for four hours—and get a patent on the new and improved drug.

Kirking said therapeutic interchange might prove to play a bigger role in balancing the desire to reduce costs with the need to provide effective medication. Therapeutic interchange involves moving a patient from one drug to a different but related drug, as opposed to its chemical twin generic. This can be helpful both because very similar drugs sometimes have very different prices, as well as because one drug might not have a generic equivalent, but a related drug might. That could lead to first moving the patient from one brand-name medication to another, then to the generic equivalent of the second.

While drug advertising aimed directly at consumers has developed name recognition among patients, they can often be won over to generics fairly easily if there is a financial incentive, Kirking said. They might ask for the brand-name drug but they will switch to the generic if they find that the brand-name version will leave them more out of pocket. If the switch to generics is part of a program implemented by a pharmacy benefits manager, these conversions can happen quickly. However, the issues surrounding changing the actual drug entity are even more complex than a generic switch. For further information the reader is referred to the statement of Larry Norton, President of ASCO, summarized in Annals of December 2001 and available in full at http://energycommerce.house.gov/107/hearings/09212001Hearing371/Norton615.htm

	The French approach to control of health expenditure and European denomination inconsistency

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The French Parliament debated in October–November the budget of the Social Security, which includes health. Among the modifications introduced is an encouragement for prescriptions using the International Common Denomination of Drugs (DCI). One should note here that in a climate where a common European market is being built, drugs continue to be registered with various names in different EU countries, leading to some difficulties for patients who travel and for health personnel attending many meetings. The deputies also increased the contribution to the finances of the Social Security that drug companies have to pay in relation to their advertising expenses. These efforts clearly indicate that the socialist laws which should have solved many of these issues have been ineffective, as seemingly admitted by Bernard Kouchner, the Health Minister. The Finance Minister Elisabeth Guigou stated that public hospitals would have an increase in their 2002 budget, with 440 million Euros to finance badly needed renovation of their structures. Meanwhile, the private clinics were on strike because their financial structure (tightly controlled by the government) does not allow them to give to nurses a salary equivalent to that given by the public hospitals. This leads to dramatic shortages in personnel in some areas.

	Good quality information for the patient and the public: a new ESMO initiative

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One of many issues we face in medicine is our inability to communicate effectively, maybe not always with individual patients, but certainly with patient groups and the lay public in general. Patient groups or patient caregiver groups have been created, addressing many of the more chronic diseases, from diabetes to asthma, and of course in oncology. The October issue of CancerFutures, a new journal launched by Springer-Verlag and edited by Maurice Schneider, contains articles related to patient advocacy movements.

ESMO has not waited idly for this and at the instigation of its new President Heinz Ludwig it has been preparing a major initiative for its Nice meeting in October 2002. ESMO shall convene representatives of many groups and individual patients for several sessions, in order to learn from them, and share its knowledge with them. And certainly ESMO will involve journalists from major magazines in Europe, in the hope that they will continue the excellent educational role they have, as exemplified by Marie-Claire in its October 2001 edition. This magazine has a large circulation in France and it has discussed many of the issues related to patient self-medication. It gave as an example the frequent problem of laxative abuse in France. Commandments of self-medication were put forward: all drugs have side effects; symptoms lasting more than 5 days need medical advice; expiry dates on drug boxes should be respected; do not take any drug without medical advice in case of pregnancy or if you are breast-feeding; do not mix drugs, they may interact (remember the cholesterol lowering agents?); do not drink alcohol if using ‘over-the-counter’ drugs; respect the recommended doses; do not expect that what worked for the same symptoms in the past, in yourself or a friend, will work now. This seems ‘too simple’? It is not, all those who treat outpatients know it too well.

	Nobel prizes: is it not ‘more of the same’?

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The distinguished ceremony took place before Christmas, and the awardees had a wonderful time with their families and friends. But now that the rejoicing is over, one wants to take a somewhat more critical view. Of course we admire the superb work of Sir Paul Nurse, Leland Hartwell and Tim Hunt. But let us take a cool look at the prizes for ‘Medicine’ of the past 20 years. How many have gone to clinicians, epidemiologists, nurses...? The prize should be renamed the Medical Sciences prize. To quote a Lancet editorial from 1999: "Nobel wanted to reward people who conferred the greatest benefit to mankind. To honour his wish fully, clinical and epidemi-ological research must be appreciated as much as basic science."

The fact is that this seems very much the same problem as that of research funds for clinical work. If universities are to be allowed to continue independent academic clinical research, their funding must be secured. But many granting agencies often rely on very distinguished colleagues who are covered with honours because of their work in basic research. Furthermore, at least two major European agencies use, in their decision making analyses, the total impact factor of the papers published by the group requesting a grant, and unfortunately the nature of this type of calculation leads to a huge bias in favour of basic research.

Can we really compare the impact factors of Cell (36.242 for 1999), Science (24.595), Nature (29.491) and the EMBO Journal (13.973) with those of the Lancet (10.197), New England Journal of Medicine (28.857), Annals of Oncology (3.195) and European Journal of Cancer (2.537)? Even grant requests of EORTC are liable to suffer from this type of bias, in spite of the recognized importance for the treatment of cancer patients that its independent work, published in European Journal of Cancer, Annals of Oncology, New England Journal of Medicine, The Lancet, Journal of the National Cancer Institute and Journal of Clinical Oncology has had and will have. On another issue: one can publish the results of a 4000 patient phase III study once, after 8 years of hard work, and this makes it into a prestigious journal. But this major publication will have fewer total points than the many phase I and II studies which barely made it for publication in excellent journals of lesser artificial ranking. The impact of this question will be fully discussed at the Second EORTC Strategic Scientific Meeting in Brussels, 26–28 March, 2002 (more on this under www.eortc.be).

	Perhaps not everyone knows that...

Top The XXX stories of... It is about patents... Generics again... The French approach to... Good quality information for... Nobel prizes: is it... Perhaps not everyone knows... References

 
...18F-FDG-PET is able to detect metastases of differentiated thyroid carcinoma (DTC) undetected by 131I post-therapy whole-body scanning in patients with elevated thyroglubulin (Tg) levels. This is the conclusion of a prospective study, from Hôpital Antoine Beclere, Clamart, France, in which the ability of FDG-PET to detect metastases in DTC was assessed. Some 37 patients with DTC who had undergone total thyroidectomy and radioactive ablation and presented with persistent disease, assessed from elevated Tg levels and negative results of whole-body scans performed after therapeutic doses of 131I, were divided into two groups on the basis of detection of residual disease by conventional imaging techniques. Group 1 (n = 10) had positive findings by conventional imaging, while group 2 (n = 27), had negative findings by conventional im-aging. In group 1, FDG-PET confirmed 17 of 18 previously known tumour sites and detected 11 additional sites, while in group 2, FDG-PET findings were positive in 19 of 27 patients with no previously detected metastases. These findings led to changes in the management of 29 of the 37 patients [1].

...a number of hypoxia-responsive genes, which are novel candidates for hypoxia-driven angiogenesis, have been identified using serial analysis of gene expression (SAGE) to examine the transcriptional response to hypoxia of human glioblastoma cells. Researchers from Duke University Medical Center found that from the 24 504 unique transcripts expressed, 10 new hypoxia-regulated genes were detected. All of these induced angiogenesis, to a greater extent than vascular endothelial growth factor. In addition studies using various tumour cell lines showed that the genes also responded to hypoxia in breast and colon cancer cells and were activated by hypoxia-inducible factor 1, a key regulator of hypoxic responses. The induced genes were found to include hexabrachion, an extracellular matrix glycoprotein; stanniocalcin 1, a calcium homeostasis protein; and an angiopoietin-related gene [2].

...in a study designed to determine the long-term efficacy of recombinant adeno-associated virus (rAAV) vector-mediated gene therapy in newborn mice with the lysosomal storage disease, mucopolysaccharidosis type VII (MPSVII), a significant incidence (six of 59 mice) of hepatocellular carcinomas and angiosarcomas was observed. Since these tumour types had not been observed previously in long-term studies of MPSVII mice using recombinant enzyme or bone marrow transplantation, attempts were made to ascertain whether mouse strain or b-glucuronidase expression confers susceptibility to tumour formation. Histopathological examinations of untreated normal mice, untreated MPSVII mice, and normal mice overexpressing human b-glucuronidase for the presence of tumours and increased hepatocyte replication, failed to show that MPSVII mice or mice overexpressing human b-glucuronidase are susceptible to tumour formation. However, the authors, from the St Louis University School of Medicine, caution that the number of animals examined is too small to draw defini-tive conclusions and that the tumorigenic potential of rAAV vectors must be rigorously determined in long-term in vivo studies [3].

...New Zealand fire fighters show an increased risk for testicular cancer. This is the conclusion of an historical cohort study of mortality and cancer incidence of all paid New Zealand fire fighters, from 1977 to 1995, conducted by Kenepuru Science Centre, Porirua, New Zealand. Testicular cancer was the only cancer for which the study provided evidence of an increased risk, with a standardised incidence ratio for 1990 to 1996 of 3.0 (95% CI 1.3 to 5.90). There was no evidence that fire fighters were at increased risk from any particular cause of death. The reason for the increased risk is unknown, and it should be noted that other studies of fire fighters have not identified testicular cancer as an occupational disease [4].

...even though the International Agency for Research on Cancer (IARC) identified sufficient evidence of the carcinogenicity of degraded carrageenan in animals to regard it as posing a carcinogenic risk to humans in 1982, it continues to be used as a thickener, stabilizer and texturizer in a variety of processed foods, such as ice cream, yoghurt and cottage cheese. Now a review, from the University of Iowa College of Medicine, of the association between exposure to carrageenan, a gum polymer derived from red seaweed, and the occurrence of colonic ulceration and gastrointestinal neoplasms in animal models has suggested that exposure to un-degraded as well as to degraded carrageenan is associated with the occurrence of intestinal ulcerations and neoplasms. Although the US Food and Drug Administration considered restricting dietary carrageenan in 1972, these restrictions were not passed and carrageenan continues to be viewed as ‘generally regarded as safe’ [5].

...the power outputs of laser pointers available in the USA do not appear to exceed 5.0 mW, the Food and Drug Administration standard for this class of device. Researchers, from the Southern California College of Optometry, tested a sample of 29 commercially available red diode laser pointers from a variety of sources and measured power outputs with an optical power meter with the sensor placed 5.0 cm from the laser. All pointers were fitted with fresh batteries. Each laser was turned on for 60 s and a reading was taken every 10 s. The power output of lasers used as packaged was found to range from 0.7 mW to a high of 3.9 mW. However, alterations to some of the lasers were found to increase the output to slightly more than 5.0 mW [6].

View larger version (123K): [in this window] [in a new window]   ESMO President, Heinz Ludwig.

View larger version (115K): [in this window] [in a new window]   Sir Paul Nurse.

	References

Top The XXX stories of... It is about patents... Generics again... The French approach to... Good quality information for... Nobel prizes: is it... Perhaps not everyone knows... References

2. Lal A, Peters H, St Croix B et al. Transcriptional response to hypoxia in human tumors. J Natl Cancer Inst 2001; 93: 1337–1343.[Abstract/Free Full Text]

3. Donsante A, Vogler C, Muzyczka N et al. Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Ther 2001; 8: 1343–1346.[ISI][Medline]

4. Bates MN, Fawcett J, Garrett N et al. Is testicular cancer an occupational disease of fire fighters? Am J Ind Med 2001; 40: 263–270.[ISI][Medline]

5. Tobacman JK. Review of harmful gastrointestinal effects of carrageenan in animal experiments. Environ Health Perspect 2001; 109: 983–994.[ISI][Medline]

6. Lamotte J, Fife J, Lee A, Hemenger R. The power output of laser pointers: do they exceed federal standards? Optom Vis Sci 2001; 78: 525–528.[ISI][Medline]

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