薬剤臨床試験のアウトソーシング/米国医療事情 グローバル化

画像 薬剤臨床試験のアウトソーシング
 臨床試験のグローバリゼーション。
 裕福な国家のために使われる薬が、途上国の人々で試験されることは倫理的な問題がある。外国人のボランティアが、経済的な補償や無料治療の約束によって、臨床試験に参加することに過度に影響される可能性がある。低所得の国が高所得の国の臨床試験工場であると想像したくはない。
 しかし、何人かの批評家は、広範囲に及ぶ倫理・科学の問題の確かな証拠を提出しないで警告を出すために、作者が過度に割り切ったデータ発掘法を使ったと言う。米国以外のより多くの場所で研究が行われているのだろうか、それは悪いことなのか?
 メルク社のGardasil(HPVワクチン)は、発症率が高いコスタリカで臨床試験が行われた。これはむしろ良い例にあたるだろう。
 いずれにしても、海外での臨床試験は増加しており、ボストンにあるFDA薬剤開発研究タフツセンターの報告では、最近10年では臨床試験を監督する米国が本拠地の研究者の割合は減少し、FDAに登録される海外の研究者の数は増加している。FDA登録された米国を本拠とする臨床研究責任者の割合は1997年の約86%から2007年の約54%へと減少した。
 環境や遺伝的背景の違いが薬剤代謝の違いを生じる可能性はあることでは意見は一致しているが、重大な懸念ではないと考えられている。
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主要薬剤の国内自給の確立を/米国医療事情 国家安全保障
http://kurie.at.webry.info/200901/article_36.html
急拡大するインドの代理出産ビジネス
http://kurie.at.webry.info/200803/article_18.html
子宮のアウトソーシング Outsourced Wombs
http://kurie.at.webry.info/200801/article_12.html
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Outsourcing of Drug Trials Is Faulted
http://www.nytimes.com/2009/02/19/business/19clinic.html

By NATASHA SINGER
Published: February 18, 2009

As many American companies in the last decade have sent tasks like customer service and computer support to other countries, drug makers have followed suit by outsourcing clinical trials ― the human studies that determine the safety and efficacy of medicines.

Now, an article about the globalization of clinical trials, published Thursday in The New England Journal of Medicine raises questions about the ethics and the science of increasingly conducting studies outside the United States ― when the studies are meant to gather evidence for new drugs to gain approval in this country.

The article, by several Duke University researchers, suggests an ethical quagmire when drugs intended for wealthy nations are tested on people in developing countries. The authors suggest that human volunteers in foreign countries may be unduly influenced with the promise of financial compensation or free medical care to participate in clinical trials.

The report, “Ethical and Scientific Implications of the Globalization of Clinical Research,” also asks whether drug research conducted in developing countries is relevant to the treatment of American patients.

“We don’t want to imagine that lower-income countries are the clinical trial mill for higher-income countries,” Dr. Kevin A. Schulman, the lead author of the article, said in a phone interview last week. Dr. Schulman is a professor of medicine at the Fuqua School of Business at Duke, in Durham, N.C.

But some critics say the authors used overly simplistic data mining to raise an alarm, without presenting hard evidence of widespread ethical or scientific problems.

“More places outside the United States are participating in research ― is that a bad thing?” said Dr. Ezekiel J. Emanuel, the chairman of bioethics at the Clinical Center of the National Institutes of Health in Bethesda, Md., after reading an abstract of the article sent to him by a reporter.

Dr. Emanuel cited a clinical trial of the Merck drug Gardasil, a vaccine against the human papilloma virus, that was conducted in Costa Rica, where there is a high incidence of the disease. “This is the kind of case where it is a good thing.”

Whatever the interpretations, the use of offshore clinical trials is growing. In the last 10 years, the proportion of United States-based researchers who direct clinical trials registered with the federal Food and Drug Administration has declined significantly, while the percentage of F.D.A.-registered researchers outside the United States has significantly increased, according to a report in January by the Tufts Center for the Study of Drug Development in Boston.

In 1997, about 86 percent of F.D.A.-registered principal investigators were based in the United States, the Tufts study said. By 2007, only about 54 percent of about 26,000 F.D.A.-regulated chief scientists who conducted clinical trials that year were based in the United States.

Kenneth A. Getz, a senior research fellow at the Tufts center, said drug companies were looking abroad because it was often less expensive to conduct clinical trials outside the United States, and it was easier to find a large group of study subjects who had never been treated with medications.

Critics of the Duke article take issue with its methodology. The authors, for example, compare the locations of 300 clinical trials published in three leading medical journals in 1995 and 2005, concluding that the number of countries participating in studies more than doubled over that decade.

But critics question that comparison, because about 40 percent of the published clinical trials from 1995 did not indicate where the studies were conducted.

One of the authors, Dr. Seth W. Glickman, a senior scholar at the Fuqua School of Business at Duke, said he did not know how omitting those studies might have skewed the analysis.

And although the article uses the country statistics to raise concerns about the increased globalization of clinical research, the Tufts study shows that the majority of F.D.A.-regulated drug researchers are still in the United States. Offshore researchers, moreover, are represented largely by Western Europe and middle-income countries in Eastern Europe and Latin America, according to the Tufts data.

The Duke authors also write that drug research in developing countries ― where certain populations may metabolize medications differently because of environmental factors or genetic mutations ― might not be relevant for American patients. “There are issues with the interpretability of the findings,” Dr. Glickman said.

Dr. Emanuel of the N.I.H. agreed that it was possible that some offshore drug research might not be applicable to American patients. But he faulted the report for seeming to treat all foreign countries alike. Research conducted in some places outside the United States ― like Canada and Sweden ― might be perfectly relevant to American patients, he said.

“It’s not a sufficiently nuanced concern to give it credibility,” said Dr. Emanuel.

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Growth of clinical trial outsourcing raises issues
http://edition.cnn.com/2009/HEALTH/02/18/outsourced.trials/index.html
* Story Highlights
* In November 2007, one-third of clinical trials were done outside of United States
* Trials in India, for instance, carry only about one-tenth the costs
* Authors say genetic makeup in countries may affect response to medication
* Report written in the New England Journal of Medicine
* Next Article in Health ?

By Tom Watkins
CNN

(CNN) -- The practice of moving research involving human subjects from wealthy countries to less wealthy countries has grown in recent years, raising a number of ethical and scientific issues that need to be addressed, researchers said in a journal article Wednesday.
More and more clinical trials are being moved to less wealthy nations, a medical journal article reports.

More and more clinical trials are being moved to less wealthy nations, a medical journal article reports.

"The question is proportionality," said Dr. Kevin Schulman, director of the Center for Clinical and Genetic Economics at Duke University Medical Center in Durham, North Carolina, and one of the study authors. "We should test products where we are going to market them. The populations who take risks to participate in clinical research should be the ones that we anticipate will get the benefits of the research."

He and his co-authors reported in the New England Journal of Medicine that in November 2007, about one-third of clinical trials (157 of 509) were being carried out entirely outside the United States, many of them in developing countries. Between 1995 and 2005, the number of countries where such trials were being carried out more than doubled, while the number in the United States and Western Europe decreased, the researchers at Duke University said.

The shift appears to have been driven at least in part by economics -- a top medical center in India charges about a tenth what a second-tier U.S. medical center would charge per case report, the authors said.

Another incentive to move such work abroad: other countries' regulatory environments can be less burdensome. The authors reported one study that found only 56 percent of 670 researchers surveyed in developing countries said their work had been reviewed by a local institutional review board or a health ministry.

Another study reported that 18 percent of published trials carried out in China in 2004 adequately discussed informed consent for subjects considering participating in research.

In addition, recruitment of study subjects can be easier in developing countries, where a trial subject may get more than a year's pay to participate or participation could be his or her sole means of being able to get treatment, the authors said.

Transparency is yet another issue.

"We know little about the conduct and quality of research in countries that have relatively little clinical research experience," they wrote.

Schulman put it more bluntly.

"We've seen problems with people cheating on clinical trials," he said.

He acknowledged that similar problems have arisen in the United States, but said such misdeeds were less likely to be found out when they happened abroad.

Of critical importance is the fact that some populations' genetic makeup may affect their response to medication, the authors said. For example, they said, some 40 percent of people of East Asian origin have a genetic trait that impairs ethanol metabolism and limits response to nitroglycerin treatment.

"This finding may affect the relevance of trials involving cardiac, circulatory and neurologic disorders that are treated with nitroglycerin or nitric oxide-dependent therapies," they said.

The authors called for regulations governing trials to be reduced while ensuring ethical conduct, for greater use of centralized oversight boards and for research contracts to be written using standardized terms.

"Key strategies for clinical trials should be outlined in formal clinical-development plans, publicly vetted, and submitted to regulatory agencies," they said.

Alan Goldhammer, vice president for scientific and regulatory affairs at the Pharmaceutical Research and Manufacturers of America, said the industry will study the suggestions and weigh whether to incorporate them.

"We're constantly taking a fresh look at all our documents and revising them as appropriate," he said. "The last thing any company wants to have happen is for a trial site to be called into question and that data then not used for review by the regulatory agency, which could put its approval status in limbo."

The matter has gained in importance with the announcement by the Obama administration that the government will carry out tests to determine which drugs work best.

A spokeswoman for the Food and Drug Administration, who said she could not be identified because she had not sought permission to talk to the news media, said the agency has begun training and educating regulators in countries where clinical trials are being carried out for companies that are seeking U.S. approval for their drugs.

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NEJM Volume 360:816-823 February 19, 2009 Number 8

Ethical and Scientific Implications of the Globalization of Clinical Research

Seth W. Glickman, M.D., M.B.A., John G. McHutchison, M.D., Eric D. Peterson, M.D., M.P.H., Charles B. Cairns, M.D., Robert A. Harrington, M.D., Robert M. Califf, M.D., and Kevin A. Schulman, M.D.

Economic globalization is an important development of the past half century. Proponents of globalization highlight the benefits of greater economic growth and prosperity; critics point to the exacerbation of economic disparities and the exploitation of workers, particularly in developing (i.e., low- and middle-income) countries.1,2 Pharmaceutical and device companies have embraced globalization as a core component of their business models, especially in the realm of clinical trials. This phenomenon raises important questions about the economics and ethics of clinical research and the translation of trial results to clinical practice: Who benefits from the globalization of clinical trials? What is the potential for exploitation of research subjects? Are trial results accurate and valid, and can they be extrapolated to other settings? In this article, we discuss recent trends in and underlying reasons for the globalization of clinical research, highlight important scientific and ethical concerns, and propose steps for the harmonization of international clinical research.


Figure 1. Open Phase 3 Clinical Trials Sponsored by the 20 Largest U.S.-Based Pharmaceutical Companies, as of November 2007.
The size of the pharmaceutical companies is based on total annual health care revenue.9 The number of clinical trial sites (Panel A) includes each location where a study is recruiting patients. The number of clinical trials (Panel B) includes any trial conducted in a country that has at least one site. The data were abstracted from the ClinicalTrials.gov Web site in November 2007.

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