Mark Pine

Yesterday, HHS released recommendations for how the Secretary will spend $400 million in funds for comparative effectiveness research (CER). The report was prepared by the Federal Coordinating Council for Comparative Effectiveness Research.

I’ve posted several times on the importance of CER research for improving effectiveness and safety, and reducing the cost of medical treament. Universal health care in the United States will not be affordable or worthwhile unless such research is done.

The program outlined by the council looks good so far. Plans include four major categories of spending: Comparing medicines for a specific condition or discharge process; training new researchers and developing methodologies; building a data infrastructure with practice-based data networks, linked medical administrative databases, and patient registries; and creating tools and methods to translate comparative effectiveness results into practice.

The council website includes a form for public comment on the plans. This morning, I used the form to submit a recommendation to emphasize the third element of the CER plan—the data infrastructure. I’ve long entertained the idea and hoped that the government would construct a database to include all the patients, illnesses, and treatments in the entire nation. It might be difficult to do, but I don’t think it impossible. We should start the effort to create such a data structure now.

Here is the text of my comment to the council:

I’m extremely heartened by the federal CER program, which has long been needed and is long overdue. As an FDA medical reviewer (now retired), I analyzed comparative effectiveness and safety research related to drugs, and I agree that much more of that work needs to be done.

The program seems well thought out and well designed. But I would like to emphasize to you the third element of the strategic framework: “CER Data Infrastructure, e.g., developing a distributed practice-based data network, linked longitudinal administrative or EHR databases, or patient registries.” This has huge potential, provided that the scope is adequate.

In the last 30 years, effectiveness/safety research has emphasized the performance of clinical trials. The gold standard of clinical research is considered the RCCT, the randomized controlled clinical trial. Such trials will constitute the first element of your strategic framework. But despite three decades of well-designed investigations, most important issues of comparative effectiveness remains unresolved.

Clinical trials are fundamentally limited in what they can accomplish. They are expensive and time-consuming, and their scope is focused, limited, and piecemeal. They are often artificial and unrealistic. And although they are considered the gold standard, they are often subject to as much bias, manipulation, and lack of precision as any other kind of research.

On the other hand, a database of medical practice, which includes patients, diagnoses, interventions, courses, and outcomes, has many advantages. Research can be done more easily and quickly and at much less expense, once the database is up and running. Questions for investigation can easily be modified as ongoing results become available. Often questions that weren’t even asked may emerge during research and be added to the protocol.

The main problem with such research is the sampling issue. Does the database include only a sample of the patient/disease population, and is the sample biased? (The sampling problem is one of the main problems that the RCCT is supposed to resolve, although it often does not really do so.)

I would like to urge you, therefore, to make it a first priority in the strategic framework to develop a practice database that is universal. The federal government should try to establish a data infrastructure that includes all—all patients, all diagnoses, all interventions, all courses, and all outcomes in the nation. This may seem impossible to do. But I am confident that in this age of gigahertz computers, terabyte bandwidth, and instant Internet connectivity, it can be done.

Such at database would make it possible to ask and answer a research question by investigating the complete set of cases to look at. There would be no possibility of biased sampling. Questions could be formulated and investigated quickly and easily. Precise and detailed answers could be determined—because all the cases would be investigated.

The benefits to our society would be enormous.

Just Saturday, the NY Times reported that cancer research in America, which is supported by the National Cancer Institute has been conventional, and advances are usually marginal. Science reporter Gina Kolata wrote that grant reviewers are timid about taking chances and usually refuse to fund projects that might not work out. Consequently, “the fight against cancer is going slower than most had hoped, with only small changes in the death rate in the almost 40 years since it began.”

Yet, the very next day, another Times science reporter, Nicholas Wade, wrote about a breakthrough treatment method developed in Australia. Is this another case of American medicine falling behind the rest of the world?

The technique described online in Nature Biotechnology uses anticancer drugs packeted in “minicells” that bud out and pinch of from altered bacteria. The outer membranes of the minicells are embedded with antibodies that bind to tumor cells, and the interiors are stuffed with chemotherapy drugs.

The technique reported in the journal used two infusions of minicells to destroy tumors. In the first, the packets were filled with small RNA molecules designed to enter the tumor cells and bind to larger RNA molecules, thus shutting down the translation tumor-resistance genes into the corresponding proteins. The first infusion, therefore, disables the tumor’s ability to resist chemotherapy. In the second infusion, the minicells carry a tumor-killing drug—in this case doxorubicin—to the tumor. Because the minicellular envelopes are covered with antitumor antibodies, the drugs are delivered to the cite of the tumor, sparing other cells of the body from drug-related toxic effects.

The researchers demonstrated the technique works in the laboratory to eliminate tumors transplanted into mice and dogs. Whether the technique will work against actual human cancers remains to be discovered. Many anticancer therapies show great potential against cancers in the laboratory but fail when used against real illness. Model tumors in laboratory animals are carefully selected, and the experimental treatment conditions are artificial and well-controlled. Actual clinical situations involving real patients and tumors are uncontrolled and highly variable. Oftentimes differences between the lab and the reality defeat a promising treatment.

Nevertheless, the researchers did achieve the destruction of drug-resistant tumors in living animals, a dramatic advance that may produce a breakthrough in cancer therapy.

“Swine flu cases pass a million,” the NY Times reports this morning. So the need for a vaccine grows each day.

This week Kathleen Sibelius, Secretary of HHS, announced the department will use an advanced technique to produce a vaccine. In the method, developed by Protein Sciences, a swine flu gene is inserted into another virus that attacks insects but not humans. The gene multiplies rapidly in insect cells, which are then used to make a vaccine. The technique is expected to produce swine flu vaccine on a commercial scale more rapidly and safely than older vaccine production techniques. The government has contracted for least 50 million doses to be available by Fall.

Unlike ordinary seasonal flu, swine flu infections are continuing to spread this summer, after the end of the 2008-2009 flu season. Federal officials say that the thousands of new cases appear every week, and possible outbreaks have occurred in 32 summer camps. Most cases, though, are not tested, so the numbers are estimates. Less than 1% of patients are hospitalized and about 1 in 10,000 die.

Nevertheless, the H1N1 swine flu pandemic is causing considerable concern. Severe illness often strikes young people. The median age of those hospitalized with flu is just 19. Risk factors for severe illness include morbid obesity, pregnancy, asthma, diabetes, and immune system disorders. And according to the Times article, 2% of the “elderly” who contract the disease succumb. The A/H1N1 serotype is the strain that caused the 1918 swine flu epidemic that killed tens of millions of people, and that fact has caused concern, too.

The virus will likely continue to move slowly through the U.S. and other northern countries this summer, as well spread widely in the southern hemisphere, which is now experiencing winter. Reports of the flu outbreaks have come from Australia, as well as from Argentina, where it has infected both humans and animals. There is some concern that the virus will continue to evolve as it spreads, and that it could become more adapted and more lethal to humans by the time 2009-2010 flu season begins in the northern hemisphere.

A Scientific American article in July, published online yesterday, suggests that in comparison to chimps, humans have larger brains and more intelligence because they develop more slowly and mature later. The tardy pace wins the intelligence race.

This possible explanation arises from a gene expression study that appeared in PNAS last April. The researchers at Wayne State University School of Medicine used gene chips to investigate the developmental timing of gene expression in the prefrontal cortex of humans, chimps and rhesus monkeys. They did so by taking tissue samples the dorsolateral cortex of postmortem brains of individuals who died at different developmental ages.

They identified 299 genes common to the three species that change in level expression with age in all three. In the case of 38% of the genes, human expression levels rose later in developmental life than with chimps and monkeys. In comparison, for 15%-25% of the genes (i.e., about half as often) human expression rose earlier or chimp expression rose later. (The expression levels in the monkeys were used to set baselines for comparison.)

The same evening as the SciAm report, the PBS program NOVA re-aired a 2008 documentary “Ape Genius” on the remarkable findings of chimp intelligence produced at Germany’s Max Planck Institutes. The video showed chimps demonstrating cognitive abilities in the behavioral laboratory, including problem solving, cooperating with other chimps, and learning by imitating other chimps. The program also showed wild chimps in Tanzania cooperating and learning from each other to such extent that one of the scientists interviewed claimed their group behavior fit the anthropological definition of the term “culture.”

My interest in this subject grows out of my fascination with nature of consciousness. I believe that animals are conscious as humans are. However, the complexity of conscious experience varies by species, and human consciousness is by far the most sophisticated and multifaceted. Research such as shown on the NOVA program demonstrating human-like cognitive behaviors in chimps is consistent with this view, I think.

The coincidence of the program and the SciAm article makes me wonder what about delayed development, prolonged immaturity, in humans might account for the intricate and manifold nature of human consciousness? The program showed experiments demonstrating the remarkable intelligence of chimps, but it also showed one thing that chimps do not learn to do—something human children do learn to do between ages 3 and 4.

It was called the “triangle.” A mother can teach her human infant about another thing. The pattern is triangular, consisting of the mother (teacher), the child (learner), and the object (thing learned about). Chimps cannot learn in this way. They are able to learn by watching other chimps and imitating. But one chimp cannot teach another chimp about some third thing the first chimp knows about.

In terms of delays in development, it suggests, I think, that in humans there persists for a longer time a certain plasticity of brain connectivity. Perhaps what is prolonged is the period of time that axons grow actively to form synapses and make multiple synaptic connections per axon. Unfortunately, it’s not possible to know from the Wayne State research, since it investigated expression levels of the genes but not what the genes do.

A recent article in Scientific American online questioned the safety of Roundup, the widely used herbicide. The problem wasn’t so much with the active ingredient, glyphosate, as with the product, which mixes the plant toxin with a surfactant that helps it to penetrate the cells of organisms—both plants and animals. This is true because all cells are contained in sacs made of lipids, which can be degraded by the detergent action of surfactants.

As a result of increased penetration, the toxicity of Roundup is “amplified,” in the word used in the article. According to French molecular biologists led by Gilles-Eric Seralini at the University of Caen, who studied the toxicity of Roundup, “One specific inert ingredient, polyethoxylated tallowamine, or POEA [a surfactant], was more deadly to human embryonic, placental and umbilical cord cells than the herbicide itself.” They suggested that residual levels of the herbicide found in crops could cause cell damage, and that in humans, “Roundup might cause pregnancy problems by interfering with hormone production, possibly leading to abnormal fetal development, low birth weights or miscarriages.”

I recently used a glyphosate product on my driveway and on some aggressive ivy. So I was very interested in the article and the discussion. One of the commenters on the article was a Monstanto toxicologist, Dan Goldstein. I must say that I appreciate that he took the time to respond thoughtfully.

To me, his strongest argument against the conclusions of the researchers is: “Naked cells in the bottom of a Petri dish are protected only by the cell membrane- made of fats- and guess what- if you put detergent on them, they don’t do so well.” In other words, the effect seen by the French scientists might be a form of toxicity that would be found with any effective surfactant—perhaps even one used in household detergents.

But on the other hand, the article reported: “Seralini said the cells used in the study are widely accepted in toxicology as good models for studying the toxicity of chemicals. The fact is that 90 percent of labs studying mechanisms of toxicity or physiology use cell lines, he said.” In other words, Seralini’s methods are among the ones generally used to test the toxicity of products. We have no reason to reject his conclusions just because he used cells in Petri dishes.

The bottom line for me is to be extremely careful using this stuff (and all commercial toxins). I will probably use less glyphosate in the future.

As a former FDA reviewer, I know that regulatory approval does NOT guarantee safety. It usually guarantees no disaster. But sometimes that’s not even true (e.g. Vioxx). We should take all claims of the safety of potentially toxic products with a grain of skepticism. We must use the products as the directions say and as sparingly as possible.

We’re in the middle of one divisive debate on health care reform—whether to establish a government-sponsored public health insurance option to compete with private sector health coverage. And we’re now starting another argument: Whether to have the government sanction and fund comparative effectiveness research on treatments.

The Obama Administration and the Congress have begun efforts to focus on the effectiveness of medical treatments, in terms of both therapy and cost. Today, DHHS named the members of the Federal Coordinating Council for Comparative Effectiveness Research, which was established as part of the American Recovery and Reinvestment Act, Obama’s economic recovery legislation that passed earlier this year.

The announcement explained that the research will examine the strengths and weakness of various medical interventions to give clinicians and patients more information for decisions and thus improve the performance of our health care system. Members of the committee will be officials of federal agencies with medical expertise, including CDC, CMS, AHRQ, DOD, VA, and others.

Bills now in the House and Senate presented by Democrats deal with comparative effectiveness research. H.R. 2502 introduced in May establishes a non-government, nonprofit corporation, the Health Care Comparative Effectiveness Research Institute to evaluate and compare “the clinical effectiveness, risks, and benefits of 2 or more medical treatments or services.” S.1213 introduced in the Senate this month similarly establishes a non-government, nonprofit corporation, the Patient-Centered Outcomes Research Institute to evaluate and compare “the implications and outcomes of 2 or more health care strategies.”

Some of the best examples of the need for this kind of investigation are copycat drugs. I posted about this subject last February, when the recovery bill passed. In the case of common medical conditions, there’s usually a large market for a certain class of drug, and consequently, many companies try to get a piece of the action. Since it may cost a billion dollars or more to develop each new drug, in addition to hundreds of millions more to advertise it, this situation significantly drives of the costs of developing medicines—costs which get added to our health care expenses. But all the drugs of a class do much the same thing, so there’s little to be gained and much money to be wasted from all this developing and marketing.

One thing would help immensely: If objective comparative effectiveness research were done to test all the drugs of class one against the other, then our health system would enjoy one benefit of so much expensive drug development—we’d know which drugs are best to use.

But the gains would be even greater. A drug company usually knows long before a research program is half completed how its new drug will likely compare with the others. If it won’t be clearly superior in some way to another drug already approved and on the market, the company will likely choose not to go forward and expend the huge amounts of money.

The major drug industry organizations (PhRMA and BIO) have put out position papers nominally supporting comparative effectiveness research. But since such studies would very often show their products to be less effective than others, we should question their sincerity. Indeed both organizations emphasize that comparative research should examine all kinds of medical therapies, not just drugs, and it should not focus on “cost-containment alone.”

Obstacles to progress on this front have come up in Congress in the last few days. Republicans in both the Senate and House have introduced bills (S.1259 and H.R.3002) to prohibit “the use of data obtained from comparative effectiveness research to deny coverage of items or services under federal health care programs.” The bills say, in effect, “OK, let’s do the research, but let’s make sure the federal government can’t use the results of the research to target federal funds to pay for more effective and less costly treatments.”

This kind of struggle is sure to arise again and again in the coming weeks, as health care legislation moves through Congress. Some legislators, mostly Democrats, will fight to make health care more beneficial for patients. Others, mostly Republicans, will fight to preserve the financial benefits the system gives to companies and providers.

Republicans and right-wing commenters criticize the president for not condemning the Iranian regime. What more do they want? Iranian people throughout the nation have risen up in a “green revolution”. The theocratic government is discredited as never before since it came to power.

Indeed there may be an “Obama effect” helping to empower the Iranian populace, who are tired of Iran’s isolated, near-pariah position among nations and want to see a response to Obama’s speech in Cairo and an opening by their government to the new American administration. Immediately following the election on June 13, the SF Chronicle raised this possibility. Then came the gripping events of the last 10 days. The NY Times asked the same question on the 21st.

In contrast, Sen. Lindsey Graham, a Republican, has criticized the president for not speaking strongly enough. And Charles Krauthammer, a conservative columnist, chided Obama for being “afraid to take sides.”

Whatever Obama has or hasn’t done with respect to Iran, it has not prevented the largest confrontation between the regime and the people since the 1979 revolution. So why is he being criticized? Whatever it was, it has worked.

In an hour or two from the time I post this, the president will hold a news conference. The expectation is that he will challenge the Iranian regime more forcefully than he has done so far. But you can count on him to keep his cool, measured tone. That’s our president. It’s who he is and what he does. We should get used to it. And so far, it seems to have done the trick with respect to Iran. At least it hasn’t undermined the uprising.

Results yesterday of a poll done for the NY Times and CBS News found 72% of Americans favor “the government’s offering everyone a government administered health insurance plan like Medicare that would compete with private health insurance plans.”

Among Democrats, 87% favor the idea, but remarkably, among Republicans 50% also favor the government offering such a plan. This is great news. Yet some Democratic yellow-bellies in Senate, whom you would think to support such a plan, have been scattering in the face of health industry opposition. Perhaps the results of the poll will brace their backbones and strengthen their stances.

In a long, thoughtful editorial accompanying the report of the poll, the Times took note of some Senate Democrats “so desperate to find a political compromise with Republicans — or so bullied by the rhetoric — that they are in danger of gravely weakening a public plan, or eliminating it entirely.” The editorial also explained the opposition of the insurance industry: “An inexpensive public plan would entice or drive tens of millions of Americans away from private insurance, especially if big employers were allowed to enroll their workers in an exchange [that would offer a public plan along with private plans].

The AMA also strongly opposes the public plan idea—in my view, because many of the organization’s members fear limitations on their fees and style of practice doing expensive procedures that may not be cost effective—or effective at all.

That’s the rub. The fears of the insurers and many physicians ARE well-founded. But that’s exactly why the public plan is so important. It will, indeed, be less expensive and curtail excessive fees and unnecessary treatments. That’s why these groups are afraid and it’s also why we need to fight for the public plan.

I will write my Congressional delegation again today. One of my Senators, Mikulski, is a strong public-plan advocate. I want to affirm her stance and urge the other two to join her.

The Iranian state has taken the streets back from the demonstrators. The BBC reports that Iranian police have used tear gas, live rounds, and batons to disperse protestors. Earlier CNN reported that security forces had made a “very large show of force.” Similar reports from the NY Times.

It’s not clear what it means, but it’s chilling. Until today the theocratic regime had seemed to bide time, hoping the for the demonstrations to fizzle. Instead they grew. Then yesterday the theocrat-in-chief Khamenei issued prohibitions and threats. Perhaps the people have quieted down because they’re not sure how to respond and are waiting to see. Or perhaps they’ve been cowed and the demonstrations are finally done.

In either case, it’s chilling for Iran and for the rest of the world. Unlike the PRC, who appear able to prevent any unsanctioned reporting from inside China, the IRI has allowed foreign journalists more freedom, and the Iranian people appear more adept at connecting with the wide world and getting the word out. As a result, the world has witnessed the regime turn the crank of the vise of Iranian state security as it crushed the dissent today.

What’s happening in Iran should give everyone pause. An election has been brazenly stolen. In announcing the overwhelming victory of Ahmadinajad by tallying the count of tens of millions of paper ballots in just two hours after the voting, the regime didn’t seem to give a hoot what anyone might think.

But many nations besides Iran have also mastered the modern techniques of crowd control, riot suppression, surveillance, detention, intimidation, and torture. It’s just that we’ve seen today in Iran so graphically how it can work. In America, our municipal police have also become experts at this kind of operation. And we have our own NSA to spot dissidents and watch them. In the case of dictatorships like Iran, control of communication systems, particularly cell phones and the internet, has been added to systems of surveillance and suppression.

Could this sort of thing happen in this country or some other advanced democracy? We like to think not. In America, we have our free press, and a vigorous tradition of dissent sanctioned in our Constitution.

But we’ve had our share of officials in high office who have had trouble differentiating their own security from that of the nation—Dick Cheney, George Bush II, Richard Nixon and perhaps some others. After seeing what’s been happening in Iran, I’m reminded of my longstanding feeling of unease at the technological prowess to monitor and stifle dissent that many modern governments, including our own, have gained.

With consciousness, the most difficult problem can be knowing what you’re talking about. When I use the word, as the category title of some postings and a subject of great interest, I mean the thing that lights up my mind.

The closest technical term is “qualia,” which comes from philosophy. The Stanford Encyclopedia of Philosophy defines qualia as “the introspectively accessible, phenomenal aspects of our mental lives.” Wikipedia explains:

Qualia, … from the Latin for “what sort” or “what kind,” is a term used in philosophy to describe the subjective quality of conscious experience. Examples of qualia are the pain of a headache, the taste of wine, or the redness of an evening sky.

Jogging from my home yesterday along a woodland path to a nearby beach, I thought of a new way to shed light on a confused idea about consciousness. I often get good ideas while jogging, and maybe that’s because of the clarity of the world when I’m so close to nature.

People tend to think of consciousness (if they think of it at all) as something that happens inside our skulls. People usually understand consciousness as the product of our brains. We think: You cannot not see the consciousness that’s inside my skull, and I can’t see the consciousness that’s in yours. The neuroscientist and philosopher Antonio Demasio wrote about consciousness as a kind of movie-in-the-brain (The Feeling of What Happens, 1999.)

This is a confused idea. Consciousness as the light of the mind—the fundamental aspect of mental life—is neither a product of the brain nor contained within skulls. But it is difficult to explain this. Here’s the explanation I thought of yesterday:

Jogging on the path I saw the beautiful trees, bushes and sky. At the same time I had thoughts of other things, and I also saw those thoughts in my mind—for example my daughter and my plans to meet her for lunch the next day. So I experienced two kinds of light—the light of the day illuminating the external images, and the light of my mind illuminating thoughts of my daughter. My insight was that if you think about this scientifically, the external and internal lights have to be the same light.

The light of the day comes to our eyes through photons. These particles of light, probably originating in the sun, bounce off objects and ricochet to our eyes. The photons then register on the retina, and carried by ions along axons, the impulses flow via the optic nerve to the visual cortex. In our brain something happens (not understood) to bring the images of the day to our conscious awareness.

Now consider that the same kind of thing happens when no external signal is involved. The image of my daughter originated from an internal source in my brain. The nervous processing that created that image also involved ion flows along axons.

But ion flows and interactions of ions happen through photons. In both cases—whether the image started outside my brain as light bounding off a tree or it was generated internally as a thought of my daughter—it was the ion flows and the interactions of ions through photons that gave rise to the images.

Whatever happens either external to the brain or internal to the brain, it is photons that do the happening. Photons are the vector particles of the electromagnetic force. Not only do photons bring the images of the day to our retinas, but also photons transmit the electrical impulses in our brains. Coming through the air as light, the signals move as free photons, while in the brain, the impulses flow as ions. But when the ions interact, in whatever nervous processing handles the impulses, the interaction is electromagnetic and therefore it is also transmitted by photons.

So, whether the nervous processing originates externally or internally, the electromagnetic forces that carry out the processing and bring about conscious awareness proceed through the interactions of photons.

It’s scientifically reasonable to conclude, I think, that the light of consciousness must be something in the nature of photons—their particulate nature, their wave nature, or something unknown in their nature. Photons are intimately connected with physical light, but also with the light of consciousness.

To return to my thoughts jogging yesterday: If it’s true that photons are connected to the light of consciousness, then it’s unreasonable to think that consciousness is something confined within a brain or a skull. Photons are the same whether internal to the brain or out in the world. My insight was this: The consciousness of the trees, plants and sky and the consciousness of thoughts of my daughter, which I had at the same moment, were both part of a single consciousness.

At that instant I had the thought: Consciousness is a unified thing. Both inside and outside, it is one consciousness.