The call for the CDC and WHO to release H5N1sequences misguided

This is something that has been bothering me for a little while. I think a lot of people who aren't studying biology or have had to deal with "biodiversity laws" are missing a few critical pieces of this issue.

WHO is not at fault for not releasing the Indonesian H5N1 sequences. Indonesia has very, very stringent nucleic sequence I.P. laws. All genetic material recovered there is their property. Their Convention of Biological Dviersity Law No.5 (1994) and Cultural Practices Law No. 12 (1992) effectively prevent all non-Indonesians from removing biological materials from the country for study (academic or commercial). If you are granted permission to remove the material, Indonesia is still the owner and licensee of that material. The WHO and CDC cannot release those sequences. It is not within their legal wherewithall. Nature and Science are aware of this - what's eating at me is that when the story is referenced, no one ever notes that the release of these sequences would violate Indonesia law, international patent and property conventions and make research in that country much more arduous for foreign researchers.

Indonesia is what is referred to as a mega-biodiverse country. As such,they are a hotbed for pharmaceutical research. They have stringent laws governing genetic material export to ensure that they get a return on the research that is undertaken there by corporations. Given that the same patent protections are offered pharmaceutical companies in this country, I don't have a problem with this. Everyone deserves the guarantee of a return on their investment.

WHO and CDC release of these sequences would be an act of bio-piracy, and violation of the trust and agreements between Indonesia and foreign researchers......and act that would make it much more difficult for the rest of us to acquire biological material in Indonesia and countries with similar laws, such as Brazil. Let's not forget that, despite their research and economic prowess, the WHO and CDC cannot just enter countries to gather data at will. They have to be granted permission. The release of these sequences without Indonesia's consent could make it much more difficult to research influenza on the whole (you have to remember that novel influenza strains typically emerge in Asia. Indonesia, with high influx of people annually and cultural traditions that include backyard farming makes it a logical place to conduct influenza research). If you want to put pressure on someone, put it on the Indonesian government. Their explicit permission to release these sequences is required.

I read the letter being passed around congress. Undermining the authority of other governments in the interest of medical research is not altruistic and it isn't in the majority's best interests. These sequences end up in Genbank without Indonesian holding the patents, and Western pharmaceutical companies can use them without paying fees. Academics typically don't pay fees to use sequences that have been patented by a government.....so who is really interested in the release of these sequences? Influenza anti-virals are a booming sector in pharmaceutical research. In my view, as I have stated many, many times before, the emphasis on H5N1 as a disease threat is distorted and overblown.

If this were being done with the interests of Indonesians in mind (who - incidently- are actually under immediate threat of highly pathogenic human-human H5N1 strains), governments and patenting offices worldwide would be clammering to speed any requested or required patents of these sequences so that they could be released without the concern of piracy.

Would I like to see them in Genbank. Of course.....but put this issue in perspective. Do you have any idea how many HIV sequences are held without release by pharmaceutical companies? Thousands. When people read this story do they consider how much human proteomic information relevant to TB, HIV and cancer research is being held by companies hoping to make a profit on licensing the sequences and structures? TB and HIV kill 100s and 1000s x more people annually alone than H5N1 has in the last 2 years. Again, I ask why undermine a nation and put everyone's research and health in jeopardy? If you want the sequences, put the pressure on Indonesia and make arrangements for free academic but fee-based commercial use.


I've been on a number of key blogs that have been following this story. Their front pages and links do not discuss the legal problems the CDC and WHO face in releasing these sequences. It's very possible that someone else has mentioned this and I've just missed it. Still, it's been irking me for weeks, so I just wanted to put it out there.

Did EPA Bend to Industry to Develop Pesticide Testing on Children Policy?

The Public Employees for Environmental Responsibility (PEER) claim that pesticide industry lobbyists (Crop Life America, Bayer Crop Life Science) met with the Environmental Protection Agency and the Office of Management and Budget to develop Bush's September 12, 2005 Proposed Rule on Human Pesticide Experiments. This is not, in itself, unusual. Consultations with industry, lobbyists and the public are typically required for external government policies in most western jurisdictions. What is unusual about the August 9th, 2005 meeting, noted by PEER, is that all parties reviewed the current regulatory framework for pesticide testing with the specific aim of finding loopholes that would allow for testing on children.

Quite a change in tune for the EPA. This is a department, afterall, that has traditionally legislated against all pesticide testing on children and pregnant women due to potential nervous system damage and other developmental defects. What PEER find most upsetting about the document they recovered from the August 9th meeting, are text changes to the policy that the lobbyists requested. Phrases such as "Re: kids - never say never" and "Pesticides have benefits. Rule should say so. Testing, too has benefits".

Having worked in policy, I can tell you that writers are typically urged to write policies that are worded generally and do not impede industry. The EPA is market driven, so there is extra pressure for writers to sacrifice a concise document for a policy that states benefits of the product to be regulated. That this policy allows for dosing experiments of non-pesticide toxic compounds on infants and pregnant women, however, should be sparking public outrage. This policy allows for the testing of individual compounds that compose a pesticide on the humans most likely to suffer the long-term negative effects of exposure. It actually is a step closer to the human experiments that took place in 1940s Europe, than it is the human experiments regulated by the Clinton administration. This is a gross departure from past EPA policy. The EPA's Scientific Advisory Panel and OFfice of Inspector General have spoken out against this policy.


But it's a blip in the backpage of the newspaper.

Here are the notes that tip off PEER's rage.

http://www.peer.org/docs/epa/06_26_5_EPA_HumanTesting_meetingnotes.pdf

Sacramento Bee article on the rules.

Sacramento Bee, January 24, 2006

New pesticide research rules face heavy fire
EPA calls them tough and fair; critics want human testing out.

WASHINGTON - The Bush administration would allow some limited pesticide testing on children and pregnant women under controversial rules set to be made final as early as this week. After fielding some 50,000 public comments on its earlier human-testing proposals, the Environmental Protection Agency is setting out final rules that officials call tough and fair. But California Democrats and environmentalists are raising an outcry, and courts could remain busy sorting it all out. The fact that EPA allows pesticide testing of any kind on the most vulnerable, including abused and neglected children, is simply astonishing," Sen. Barbara Boxer, D-Calif., said Monday.

The new rules would prohibit regulators from using so-called "intentional exposure" research that involved children or pregnant women. But under what regulators described as "narrowly defined circumstances," such research could still be used - if the researcher hadn't originally intended to submit the results to the EPA. The new rules require researchers to document their compliance with ethical guidelines, but exempt certain overseas tests. Testing on adults could proceed, following review by a new Human Studies Review Board that could "comment on" but not stop a proposed experiment. "EPA does not want to ignore potentially important information," the agency says in its final rule. "At the same time, the agency's conduct should encourage high ethical standards in research with human subjects." On Monday, Boxer and several California colleagues were one step ahead of the EPA, which hadn't yet formally released the final rules protecting human subjects. But a leaked draft of the new rules, spanning some 100 pages, spells out both the new regulations and how they will be presented to the public. "Message: the ethics and scientific value of human studies are topics of high public interest, and the agency has been deliberating its position," the EPA's written "communications plan" states. EPA officials could not be reached for comment Monday.

The issue is particularly important in California, where farmers and others applied 644 million pounds of pesticides in 2003. It's also closely watched by church and environmental groups, which raise red flags over human testing, as well as by manufacturers, which can rely on testing to secure necessary approval permits. "Humans process some substances differently from animals," the EPA notes in its final rule, scheduled for publication in the Federal Register. "Studies of this kind can provide essential support for safety monitoring programs. Animal data alone can sometimes provide an incomplete or misleading picture of a substance's safety or risk." The 50,000 comments received by the EPA since September showcase the level of public interest, although regulators noted that 99 percent of the comments were part of an e-mail or organized letter-writing campaign.

The American Mosquito Control Association, among others, previously advised lawmakers that human testing is necessary in order to develop new and safer chemical alternatives. Otherwise, the mosquito control group warned, diseases like the West Nile virus could spread more readily. "Let's look at things as they really are in the world around us," Sen. Conrad Burns, R-Mont., said during debate last year. " ... We do not do anything in this environment around us where there are no chemicals." Burns failed and Boxer prevailed, as the Senate in June imposed a moratorium on the EPA's use of human pesticide testing; the House had adopted a similar moratorium authored by California Rep. Hilda Solis, D-El Monte. The moratorium came following reports of some studies involving the intentional swallowing of pesticides. The moratorium is in place until the final rule takes effect, which is 60 days after publication. But if environmentalists conclude that "loopholes" will result in laws being broken, further lawsuits would likely follow.

About the writer: The Bee's Michael Doyle can be reached at (202) 383-0006 or
mdoyle@mcclatchydc.com.
This email address is being protected from spam bots, you need Javascript enabled to view it

FDA Guidance threatens health of volunteers

In April 2005, the FDA released its Draft Guidance for Industry on Exploratory Investigational New Drug Studies. This document states a new class of early clinical trials that would be conducted before full-on drug development. The new class of trial is called "Phase Zero". The logic behind this class is that it will be cost-efficient testing of potential drug compounds on human subjects for pharmaceutical companies and could reduce the number of human subjects required in later trial stages. Phase zero studies do not examine safety and efficacy of a compound. They have been developed to strictly gather data on compound targetting, action and metabolism in the human body.

Straight out of the gate - the FDA is facing a big problem.

In March 2006, a monoclonal antibody (TGN1412) developed by a German company, TeGenero, was part of one of these early trials conducted by an American company, Parexel, at Northwick Park Hospital, London. The result, well publicized now, is that 6 of 8 healthy men involved in a double blind trial of this antibody suffered terrible adverse reactions. Within minutes of injection, the men were writhing and screaming in pain (Bhattacharya and Coghlan, New Scientist. March 23, 2006). All six experienced multiple organ failure and have since developed severe head and neck swelling that has given them an "Elephant Man" appearance - an effect that may be related to the enaction of ordinarily quiesscent regulatory T cells.

It is now apparent that TeGenero was aware that this adverse affect was a possibility. Not only had an article been published in Clinical Immunology ahead of the trial, suggesting human cells may react poorly to the drug - but TeGenero's non-human primate studies indicated that TGN1412 caused severe neck swelling upon injection (Guardian, March 20, 2006). Reportedly, TeGenero and Parexel broke with informed consent. Multiple participants have reported that they were told by company representatives that animal trials had not produced adverse reactions.

The TGN1412 trial is the direct result of a market driven FDA and the illicit conduct of a pharmaceutical company.

The U.S. Food and Drug Adminstration is a market driven department, a point emphasized by the Prescription Drug User Fee Act (PDUFA) of 1992. With that legislation, the FDA instituted user fees which were put directly towards staff hires and various other resources that would speed drug approvals. They also placed themselves at the behest of the companies that pay the fees to have their drugs reviewed. An awkward situation that has led to faster approvals, but is coincident with 10% increase in drug withdrawals. The release of Draft Guidance for Industry on Exploratory Investigational New Drug Studies is a reflection of the FDA's market driven mandate and an exploitation of the potential conflict of interest that PDUFA created.

The TGN1412 trial is being characterized by the pharmaceutical lobby as bathwater (Wadman. March 22, 2006. Nature). This is, however, a trial that would not have occurred without the intitution of phase zero trials. The conduct of the parties involved in the TGN1412 trial greatly violated the rights of clinical trial subjects. This should not be reduced to an unfortunate incident that was could not have been foreseen. This should be all the reason to demand that FDA repeal this guidance in the interests of providing stronger regulatory language that better protects the rights of trial subjects.

Write to your senator. Ask to have this guidance reviewed, revised, repealed. Ask for revisions that provide greater protection to human test subjects in phase zero clinical trials.

Loosening the definition of Hypertension

It would appear that some prominent pharmaceutical companies are pushing to have the accepted standard of hypertension diagnosis loosened to include a new cohort of prospective patients.

http://www.nytimes.com/2006/05/20/business/20hyper.html?_r=1&oref=slogin


It should be noted, that this same concept was pushed in the early 1980s. When the Surgeon General gave a speech announcing that 180 mg per dL of lipoproteins would be the low end of range cut for coronary heart disease diagnosis (down from a 200+ mg per dL) an enormous overnight jump in positive diagnoses for the disease occurred.

Now, I’m not debating the importance of coronary heart disease as a health issue. Coronary heart disease is the number one killer in the Western world. Over 59 million Americans have been diagnosed and it causes 1 in every 2.4 deaths in the U.S. (American Heart Association web site). These people also represent a big market to pharmaceutical companies. Pfizer’s Lipitor, a medication to control blood pressure, has the highest sales of any prescription medicine worldwide. A drop in the standard for a diagnosis of hypertension from 140/90 to within the range of 120/80 – 139/89 stands to instantly change the diagnosis of another 59 million Americans from reasonably healthy to people who may in the market for this sort of medication.

The question here, really, is ‘is this change valid”? Where are the long-term health studies that back the position taken by the American Society for Hypertension? Do the findings of long-term cohort projects like the Athersclerosis Risk in Communities Study (http://www.cscc.unc.edu/ARIC/#) support the suggestions of these companies? It’s common for a healthy person to sit 20 mmHg systolic over their normal blood pressure reading due to dehydration. Shouldn’t the standards of diagnosis for the deadliest disease in the Western world be set by people who are not on the dime of pharmaceutical companies?

Why?

I've developed this blog to start discussions on medicine and politics. A current HIV researcher and a former policy analyst in risk management, biologic drugs and frontier medicines, I want to highlight the interface between politics and pharmaceutical development. This blog is a place to discuss the politics of therapeutic development and healthcare delivery.