The Blinne Blog

Clinical Trials in Need of Reform

More on the ongoing saga of suppressing negative results of drug trials. From the front page of today's  New York Times.

When the drug industry came under fire last summer for failing to disclose poor results from studies of antidepressants, major drug makers promised to provide more information about their research on new medicines. But nearly a year later, crucial facts about many clinical trials remain hidden, scientists independent of the companies say.

Within the drug industry, companies are sharply divided about how much information to reveal, both about new studies and completed studies for drugs already being sold. The split is unusual in the industry, where companies generally take similar stands on regulatory issues.

Eli Lilly and some other companies have posted hundreds of trial results on the Web and pledged to disclose all results for all drugs they sell. But other drug makers, including Merck and Pfizer, release less information and are reluctant to add more, citing competitive pressures.

As a result, doctors and patients lack critical information about important drugs, academic researchers say, and the companies can hide negative trial results by refusing to publish studies, or by cherry-picking and highlighting the most favorable data from studies they do publish.

But that's not the half of it. In PlosMedicine Richard Smith, former editor of BMJ, cites other way drug companies corrupt the peer-review system for evaluating clinical trials:

Examples of Methods for Pharmaceutical Companies to Get the Results They Want from Clinical Trials

• Conduct a trial of your drug against a treatment known to be inferior.

• Trial your drugs against too low a dose of a competitor drug.

• Conduct a trial of your drug against too high a dose of a competitor drug (making your drug seem less toxic).

• Conduct trials that are too small to show differences from competitor drugs.

• Use multiple endpoints in the trial and select for publication those that give favourable results.

• Do multicentre trials and select for publication results from centres that are favourable.

• Conduct subgroup analyses and select for publication those that are favourable.

• Present results that are most likely to impress—for example, reduction in relative rather than absolute risk.

Given his twenty five years of experience what's Smith's cure?

How might we prevent journals from being an extension of the marketing arm of pharmaceutical companies in publishing trials that favour their products? Editors can review protocols, insist on trials being registered, demand that the role of sponsors be made transparent, and decline to publish trials unless researchers control the decision to publish. I doubt, however, that these steps will make much difference. Something more fundamental is needed.

Firstly, we need more public funding of trials, particularly of large head-to-head trials of all the treatments available for treating a condition. Secondly, journals should perhaps stop publishing trials. Instead, the protocols and results should be made available on regulated Web sites. Only such a radical step, I think, will stop journals from being beholden to companies. Instead of publishing trials, journals could concentrate on critically describing them.

I am no fan of bigger government but for information as critical as this we need a truly independent evaluation. If that cannot be done then at least the post-marketing safety analysis should be done and paid for by the government. Letting the pharmaceutical companies do these seems to be cheaper but in the long run the savings are not worth it. The temptation to rig the system is just too great.

 

Discovery Institute Messes Up

Earlier last week I heard rumblings about the Discovery Institute playing a movie entitled the Privileged Planet at the Smithsonian. As for the content of the movie, I am less opposed than usual since it is based on cosmological rather than anti-evolutionary arguments.  For the Discovery Institute to emphasize that kind of argument is a step in the right direction in my opinion. All that being said the quality of the movie is not what I will be discussing. If you want to peruse the arguments pro and con I point you to the ASA. Both proponents and critics of ID are members and we regularly debate the merits of the arguments. But I digress...

The issue started when pro-ID blogger Denyse O'Leary trumpeted how the Smithsonian was softening to ID because they were showing the movie. I madly searched the Smithsonian web site and did not find the event she was referring to. Then on Saturday the other shoe dropped.  The New York Times ran the story Smithsonian to Screen a Movie That Makes a Case Against Evolution. In the story, neither the Discovery Institute nor the Smithsonian advanced Ms. O'Leary's thesis. The PR person mentioned donations and special events policy. A ha! A hook to Google on. I found the policy and I will proceed to fisk it because I found something utterly astounding:

The Discovery Institute apparently made an unrestricted $16,000 donation to the Smithsonian!

Their movie was a party in celebration to said contribution. If I were them there would be some very nervous lawyers in Seattle. Let's analyze the policies! [All emphasis mine]

CONTACT INFORMATION

Please contact us by phone or e-mail to inquire about having your special event at Natural History! A Special Events Coordinator will be happy to answer your questions, check availability of dates, and suggest an appropriate contribution.

Note that this is a contribution and not a fee. This will be significant later.

Mailing address:

Office of Special Events
P.O. Box 37012
NMNH 2209, MRC 139
Washington, DC 20013-7012

Street address:

Constitution Avenue at 10th Street, NW
Washington, DC 20560-0139

Phone: 202-633-1650
Fax: 202-357-1602
   E-mail: nhevents@si.edu

Staff

Ted Anderson
Director of Special Events

Tina Karl
Assistant Director of Special Events

Gwen Neild
Special Events Coordinator

Debbie Williams
Special Events Coordinator

SPECIAL EVENTS POLICY

Corporations and organizations making an unrestricted contribution to the National Museum of Natural History

STOP THE PRESSES! The Discovery Institute is now trying to say they paid a fee for a room. But, the policy is clear that this is for a contribution and more to the point an unrestricted contribution. The Smithsonian may spend the $16,000 on anything they want including promoting evolution. Denyse is also arguing that the movie was not anti-evolution. Fine. If you want to split hairs, go ahead. The Discovery Institute may be restricting themselves but there is no such restraint on the Smithsonian.

may co-sponsor an event in celebration of their gift.

There's our co-sponsor language. The sponsorship has to do with the fact they are celebrating a gift and not endorsing the giver. More later.

Your gift helps to support the scientific and educational work of the Museum. Personal events (i.e. weddings, etc.), fund raising events, and events of a religious or partisan political nature are not permitted.

This is the one positive I see for the DI here. The Smithsonian judged the movie as not religious. I've heard from those who are in contact with the Smithsonian staff they were looking for things being overtly religious. Nevertheless, DI scores some points here. Both sides are spinning this so heavy that it is hard not to get dizzy. My advise to Denyse and other supports of ID is to focus on this, because the rest is a lost cause.

Cash bars, raffles and the display or promotion of commercial products are also prohibited.

All events at the National Museum of Natural History are co-sponsored by the Museum and must be planned in conjunction with one of the Museum's Special Events Coordinators.

This co-sponsoring is a point of controversy. Denyse viewed this as an endorsement. But, according to the NY Times article neither the Discovery Institute nor the Smithsonian claim this. Further, the Smithsonian claims (and the policy confirms) that they have to co-sponsor the events.

The Special Events Coordinator will be required to approve all event plans, including invitation text, speaking program, the use of logos, and vendors. The name of the Museum and the Smithsonian Institution may not be used on any document without prior approval by the Museum.

On Denyse's blog is her invitation to the event that has the logo of the Smithsonian on it. The fact that her invite has the Smithsonian logo on it indicates that this event was under the policy. If this was some paying for the auditorium, the Smithsonian would have disallowed the use of their logo on the invite. I am assuming that the Discovery Institute is on the up and up here because if they used the Smithsonian's logo without approval then they are truly in a world of hurt.

Caterers working within the Museum must have the required $1 million liability insurance certificate on file at the Smithsonian. Although co-sponsors may work with the caterer of their choice, the Museum reserves the right to review and approve the choice of caterer in order to assure that they are capable of working safely within the Museum and are aware of the catering limitations within the building. The Museum's special events staff can also provide a list of caterers and other vendors who have successfully handled events in the Museum.

Once an event is approved, co-sponsoring organizations will receive a confirmation letter and an agreement form  outlining the basic parameters of the event and the fees. Required fees include the tax-deductible contribution[!!] and direct costs (for overtime services which are provided by the Museum).

The Discovery Institute is claiming that they were just paying fees and there was a contract. This may be the root of the misunderstanding because there is a contract involved with the policy. I'll deal with the contractual aspects later. The whole contribution stuff is addressed again. There are both fees and an unrestricted donation and this may have confused the Discovery Institute.

The event will be confirmed when the signed agreement form and full payment are received by the Museum's Special Events Office.

Given this is all confirmed by the Smithsonian, all of the above have to have occurred.

Payment is required prior to the event. During periods of high demand, a non-refundable deposit may be required. In these instances, the deposit will be considered an advance payment on the required contribution.

For a complete copy of the Museum's special events policy, please contact us by phone or email.

DI should have done this. If I could find this out with a couple minutes of Googling their legal staff were not doing due diligence and should be fired. I say this because DI says they entered into a contract and all contracts should be approved by their legal counsel. Add to that the fact that a law professor is on staff at the Discovery Institute and the magnitude of the error becomes even more stunning.

Korean Stem Cell Study Produces More Ethical Dilemmas

Update: The researcher denies that these are fertilized eggs. Now the question becomes whether blastocysts created by somatic cell nuclear transfer (popularly known as cloning) is life or not. I am now less concerned but the fact that Dolly became a real sheep still troubles me. Reading the reactions that people have to this issue it seems I am the only one on the planet that feels better that this is cloning rather than IVF. This is still an ethical dilemma -- just not as profound as when I originally posted this.

"I think this construct is not an embryo," he said. "There is no fertilization in our process. We use nuclear transfer technology. I can say this result is not an embryo but a nuclear transfer construct." The sheep Dolly, the first adult mammal cloned, was made using nuclear transfer, in which the nucleus is removed from an egg cell, replaced with the nucleus of the animal or person to be cloned, and then fused. The egg begins dividing as if it had been fertilized and sometimes becomes an embryo.

 

A new South Korean study has announced the ability to produce immune-matched, patient-specific human embryonic stem cells (hESCs).  The good news is that would allow for less rejection. The bad news is this will increase the number of stem cell lines needed per patient. When you get into the details of the study it gets even more ominous.

There are two techniques used: injection and fusion. The mean number of injected oocytes (read human beings might be killed because these are fertilized cloned eggs [RDB note: because of the update above my conclusions are more tenative here]) per line (read patient because every patient will want a matched stem cell line) is 16.8 and 13.8 if the donor is less than 30 years old. The numbers are 11.7 and 10.0 for fusion respectively.

The difference in success rate with respect to age is important because of how the fertilized eggs would be harvested. The common characteristic of fertilized eggs coming from fertility clinics are that the mothers are usually over 30 years old. Thus, the donors of the eggs would have to come from women who donate it for that explicit purpose.

The Koreans have already have been dogged by ethical breaches.

Seoul - When, in February [2004] , a South Korean team announced that it had derived stem cells from a cloned human embryo, its achievement was heralded as an important step on the road to 'therapeutic cloning'. But the research is now clouded by nagging questions about the source of the key resource for the experiment: human egg cells.

Korean citizens'-rights activists and bioethicists are pressing the team, led by Woo Suk Hwang and Shin Yong Moon of Seoul National University, to prove that the recruitment of women volunteers followed ethical guidelines. Nature's enquiries have also revealed troubling inconsistencies — in particular over whether the donors included junior members of the research team.

The brewing controversy could undermine the domestic public and political support on which Hwang and Moon's progress has depended (see News Feature, page 12). Any suggestion of ethical irregularities in therapeutic-cloning research could also have international repercussions, providing ammunition for activists who are opposed to the technology on moral grounds.

Therapeutic cloning involves creating an embryo by transferring the nucleus from a patient's cell into a human egg cell stripped of its own nucleus. After being grown in culture for a few days, this clone can yield embryonic stem cells, which can develop into any of the body's tissues. Because these would be derived from the patient's own cells, there should be no problem with immune rejection in using grafts derived from them to repair diseased or damaged tissues.

But cloning is very inefficient. To derive a single line of embryonic stem cells, the Korean team used 242 eggs obtained from 16 volunteers (W. S. Hwang et al. Science 303, 1669–1674; 2004). Each woman was given hormone injections to force her ovaries to superovulate, producing 12–20 eggs per menstrual cycle instead of one.

Other researchers were surprised that so many women were prepared to undergo this procedure for a research project. Side effects of the treatment can range from general discomfort and emotional stress to clotting of the veins or stroke. "It's a painful procedure and there is risk involved," says Jose Cibelli, a co-author on the paper who studies cloning at Michigan State University in East Lansing. "It would never fly in the United States."

Hwang says that the donors were motivated by a desire to push forward a promising field of medicine. "Many women are sympathetic with our research," he says. Supplementary material published online with the paper says that the volunteers were not paid, and explains that they filled in informed-consent forms detailing how the eggs would be used.

Egg donations

The donors were anonymous, but one PhD student in the team, Ja Min Koo, initially told Nature that the donors included herself and another woman in the lab. She subsequently called back and said that she had not donated eggs, blaming her poor English for a misunderstanding. But in the initial interview, she named the hospital where her donation was carried out, and explained that she had been happy to donate eggs because she already has two children.

Art Caplan, who heads the Center for Bioethics at the University of Pennsylvania in Philadelphia, argues that it would be bad practice if egg donors for such a project included students or junior employees on the research team because "it could certainly look like coercion was involved".

The information posted with the paper also states: "Neither donors nor their family, relatives or associates may benefit from this research." Koo, who was a co-author on the paper, arguably did stand to gain professionally from its publication.

Hwang denies that Koo was among the donors. But he declined Nature's requests for further documentary evidence of the procedures for recruiting the egg donors and obtaining their consent. Attempts to get more information from the Institutional Review Board at Hanyang University Hospital in Seoul, which provided ethical approval, were similarly rebuffed. Its chair, university obstetrician Moon-il Park, cancelled an arranged phone interview.

Within Korea, concern is growing about the lack of transparency surrounding the procedures for obtaining the donated eggs. "I'm doubtful women would give their eggs so easily," wrote Pil Pyul Lee, a science historian at the Korea National Open University in Seoul, in the 23 February issue of the Professors Times, a nationwide newspaper in which academics express their views on topical issues.

Lee's article also questioned the inclusion as a co-author on the paper of Ky Young Park, a plant molecular biologist formerly at Sunchon National University who is now a science and technology adviser to South Korean President Roh Moo-hyun. Park says that she has played an important role in Hwang's research over the years by advising him on public attitudes to his work with transgenic livestock, but she told Nature that she had no specific involvement with the therapeutic-cloning paper.

One of South Korea's leading citizens'-rights groups, People's Solidarity for Participatory Democracy, now says that it will look into the ethical issues surrounding the cloning paper. "We plan to pressure the government to force them to produce the documents that are required," says Jae-kak Han, who heads the group's scientific division. The Korean Bioethics Association is also pressuring the National Human Rights Commission to look into the matter.

Welcome to the brave new world. Most people oppose cloning people for spare parts but this will probably slide because the spare parts are so small. But -- make no mistake -- that is precisely what is going on here. There will be a great temptation to do this for money or pressure from families of sick relatives etc. At the end of many movies there is a disclaimer that no animals are harmed while producing the movie. Even in this limited experiment, 210 human beings may have died. Even if every stem cell line literally saved a life, an order of magnitude more of lives are lost every time.  Victor Frankenstein would be proud.

Fair Play

Chuck Colson opined concerning fair play in the Kansas evolution controversy.

Americans believe in fair play. If a football or baseball team doesn’t show up, it forfeits the game. If the defense lawyer in a trial puts on no case, the judge is likely to declare a summary judgment to the plaintiff. You play by the rules, or you don’t play.

So why have so many evolutionists apparently decided that the rules don’t apply to them?

This pattern is surfacing once again in Kansas, where you may remember a huge controversy broke out a few years ago, and the evolutionists squashed any other teaching in Kansas.

 

This time the new state board of education is holding hearings to consider revisions that a group of scientists and educators has called for. These would allow Darwin’s theory of evolution to be taught in schools, but they would permit scientific challenges to Darwinism to be taught as well.

The principles espoused by Mr. Colson are good ones. Playing fair in the midst of controversy is a very good principle. Indeed, it is a Christian one. Now for the rest of the story. Keith Miller gave the following explanation for the boycott of the Kansas hearings.

A short explanation for the decision by the scientific community throughout Kansas to not participate in the hearings.

The hearings were set up completely outside of the established process for revising science standards.  The standards revision committee has been working for nearly a year to evaluate and revise the standards.  They have received expert advise and input from both the scientific and science education community throughout the process.  The standards were posted for public and professional input and public forums were held around the state to obtain further input.  Some of the best science teachers in the state were on the standards committee.  When the committee was established the policy was set that any changes to the standards had to be by consensus, or if not, by at least a two thirds majority vote.

The result was an excellent set of revised standards that were submitted to the Board.  At this point the normal procedure would be to send the recommended standards out for external review.  However, the Board majority set them aside and supported another set of revised standards written outside of the process by an 8 member minority of the committee (the "Minority Report").  Those 8 members were all appointed to the committee by the anti-evolution members of the Board.  The Minority Report was written through meetings that were not open meetings and were not conducted through the committee process or in accordance with open meetings law.  The first Minority Report was not submitted through the commissioner's process.  John Calvert founder of the ID Net, who took the lead in writing the minority report and pushing for the hearings, appointed himself and had no official standing.  The Board members who voted for the hearings were the same individuals that had appointed the 8 members to the committee.  The three subcommittee members who are acting as jury for the hearings all hold anti-evolutionary views and publicly stated their support for the minority report before the hearings were ever held.

Thus the reasons that the scientific community has not participated are: 1) that both writing of the Minority Report, and the hearings themselves have occurred in violation of the procedure established for the standards revision, 2) that the scientific and science education community already has had extensive input into the standards and that input has been ignored in favor of the Minority Report, and 3) the hearings were not to inform the Board's decision as the position of the Board members had been publicly stated before the hearings were held.  The scientific community refused to give credibility to this process.

The scientific community in Kansas is now unified and activated in away that I have never seen in the 15 years that I have been here.  Even more so than in 1999 when we went through this before.  There is a growing understanding that the problem we face is a long term one that will require a long term effort at public education about both the nature and limitations of science.  Virtually all the science organizations in the state now recognize how important it is to publicly and clearly reject the false science/faith conflict or warfare view.  The religious community is also becoming activated.  I think that his is one of the very positive outcomes of this mess.  The Kansas scientific community is sending out a very unified voice that evolutionary science is not based on an atheistic or materialistic worldview, and that it is not in any necessary conflict with religious faith.

So, to take Colson's courtroom analogy further what do you do when a side in a conflict cheats? If the other side resigns in protest are they being unfair and do they as a result forfeit any future appeal?

 

Evangelical Scientist Fights for Evolution

Keith B. Miller, a geology professor at Kansas State University, is a leading defender of Evolution in the debate over Evolution versus so-called Intelligent Design before the Kansas State School Board. What makes Keith Miller stand out is that he is not an atheist, but rather is an Evangelical. Dr. Miller is also a member of the American Scientific Affiliation, a group of Christians who are working scientists.

The Boston Globe had the following piece on  Miller:

TOPEKA, Kan. -- As scientists who advocate the new ''intelligent design" theory stepped to the microphone at an auditorium here last week to argue that schools should teach doubts about evolution, a 49-year-old geologist sporting Birkenstock sandals and an early-Beatles haircut sat quietly in an aisle seat in the back row.

The man is an evangelical Christian who says he was ''called by God to be a geologist." But Keith B. Miller, a Kansas State University professor, is also an ardent defender of evolution -- and thus one of established science's most effective weapons in the battle to keep intelligent design, creationism, and other attacks on evolution out of the nation's public schools.

As the theory of evolution pioneered by Charles Darwin comes under assault in communities from Kansas to Pennsylvania to Georgia, Miller carries a message that plays especially well here: Faith, even fundamental Christian faith, is not at odds with Darwin.

''I say I believe God [created life], and I want to find out how," Miller said. ''They say, 'God did it; end of discussion.' "

The Kansas state school board has been ground zero for the evolution debate since 1999, when religious conservatives first drew international attention by having evolution downplayed in the school curriculum. Last week, the antievolution forces were back, arguing in hearings concluding this week that doubts about Darwin be inserted into school standards.

This time, Darwin's critics insist they are not religiously motivated creationists, but are scientists who believe that certain things in the universe, including human life, are too complex to be explained by natural causes and must be the product of an intelligent creator.

They call this theory ''intelligent design," and while they resist publicly declaring that a Christian God's hand is at work, they also suggest that proponents of a key tenet of evolutionary theory -- that changes over time can result in new species -- are atheists or secular humanists.

Stung by these charges, scientists who support evolution are trying to demonstrate that faith and science can exist side by side. ''I want to dispel their extreme worldview that there is any warfare between science and the Christian faith," Miller said.

Miller has been showing science and faith do not conflict long before this particular conflict erupted.

Still, the political winds have shifted to the right in Kansas. The state has a long tradition of moderate, economic-driven Republicanism. Now, religious conservatives are on the rise in the GOP.

That's where Miller, the evangelical geologist, comes in. If the intelligent-design advocates who testified last week downplayed their faith, Miller stressed his in order to demonstrate that orthodox religion is not in conflict with modern science.

A 15-year Kansas resident, Miller has edited a science book, ''Perspectives on an Evolving Creation," in which he and other evangelical Christians challenge intelligent design.

I highly recommend the book above, especially the chapters written by a personal friend of mine, Dr. Terry Gray. Dr. Gray presents a cogent critique of so-called Intelligent Design from an Evangelical who is an expert in Biochemistry.

But because the scientific community opted to boycott the school board hearings, anyone interested in Miller's views last week had to travel to an aging Ramada Inn across town. On Wednesday night, about 100 people did.

Advocates of intelligent design contend that evolutionary theory takes God out of the equation by concluding that all species change is random, unguided, and explained by natural causes.

''Every other code we know came from a mind," said Harris, the medical professor arguing in favor of intelligent design. ''To deduce that DNA codes came from a mind is not irresponsible."

But Miller insists that ''science does not affirm or deny the existence of a creator. It is simply silent on the existence or action of God." He accused proponents of intelligent design of resorting to a ''God of the gaps," whose hand is only visible when science can't solve life's riddles.

The description that Evolution is unguided angers Dr. Miller. The following quote of Dr. Miller from an ASA discussion board shows what motivates him:

This next change is the most extraordinary part of the ID changes to the standards.  THEY have changed the description of evolutionary science in the standards to include words such as "unguided and undirected."  THEY explicitly describe evolutionary science in the Minority Report as a Godless, purposeless, unguided process.  The standards submitted by the committee have no such language, nor do they imply anywhere that science, or more specifically evolutionary theory, is in anyway based on materialism or atheism.  It is the ID proposal, and the ID testimony before the board, that describes evolution in this way.  This angers me greatly.  The ID advocates are so intent to getting their views in the science curriculum that they are willing to describe evolution in the same way as Dawkins!  They even quoted him in the hearings to justify their definition.  I do not want Kansas children told that evolution is unguided and purposeless!!

 

Exoplanet Says "Cheese!"

The European Southern Observatory declares: Yes, it is the Image of an Exoplanet .

Astronomers Confirm the First Image of a Planet Outside of Our Solar System

Among the most essential quests of modern astronomers, taking direct images of planets outside of our solar system is certainly up there among chart-toppers. Obtaining such images of a so-called exoplanet would enable scientists to study in detail the physical nature of the object and, in particular, to analyse the composition of its atmosphere. The astronomers' ultimate goal is of course to perform such analysis for earth-sized planets, in the hope of detecting a telltale signature of extraterrestrial life.