Why FDA Approval?

With the desperate search for a coronavirus vaccine and medicines to reduce the seriousness of the disease comes a lot of discussion about FDA approval. One side argues that speed is of the essence and we need to accelerate the process. The other side argues that we can never be sure of a drug’s effectiveness without proper testing. (This will reflect some of the information from last week’s entry, “Understanding Experiments.”) 

The FDA admits, “It takes on average 12 years and over US$350 million to get a new drug from the laboratory onto the pharmacy shelf.” The first step requires about three years of laboratory testing before testing on humans. “Only one in 1000 of the compounds that enter laboratory testing will ever make it to human testing.” 

Next comes a three-phase process. First they must test for safety. Next they need 100 to 300 volunteers to test for basic effectiveness. Finally 1000 to 3000 patients in clinics and hospitals are monitored for effectiveness and to identify adverse reactions. Each phase can easily take years to complete. (And some people wonder why drugs cost so much and why the companies fight and scheme to protect their patents.)

In the interim some drugs that have been previously approved for other diseases are being tested on coronavirus patients. This practice of prescribing drugs off-label is really quite common in the US. WebMD writes, “Off-label prescribing isn't necessarily bad. It can be beneficial, especially when patients have exhausted all other approved options.”

This is why FDA approval is so valuable and why makers of so many pills, salves, ointments and medical devices are so eager to try to take credit for having cleared this hurdle. Otherwise the law requires them to post the familiar disclaimer: “The statements made regarding these products have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure or prevent any disease.” (But the disclaimer is familiar only to those who bother to read the fine print.)

If companies fail to do this, it’s not the FDA but the Federal Trade Commission (FTC) that comes after them for misrepresentation, as they did in this case – one of many that show up almost weekly.

“Under a settlement with the Federal Trade Commission, the marketers of an electrical nerve stimulation device called Quell have agreed to pay at least $4 million and stop making deceptive claims that the device treats pain throughout the body when placed below the knee and is clinically proven and cleared by the Food and Drug Administration (FDA) to do so.” (From an FTC press release.)

I checked their website and found that they no longer show the device as FDA approved (to treat or cure), but still do try to give that impression through endorsements and research posters. They continue to mention the FDA at least twice on the site, referring only to registration, not approval – big difference. In summary, the “FTC alleged that the defendants lack scientific evidence to support widespread chronic pain relief claims…” but the site lists no such disclaimer. It’s big business and a $4 million fine pales in comparison to a $350 million development cost.

That it is “100% drug free and non-surgical” while it “stimulates sensory nerves with safe and precise electrical pulses to trigger a natural pain relief response” appeals to people with chronic pain trying to avoid addictive drugs. It’s understandable how such a device would tempt people, and if placebo does the trick it might be worth $300 plus an on-going expense for fresh electrodes.

Like so many other health and medical decisions, avoiding such questionable products is all about a little research and critical thinking.

More Idiocy From the Media

Not wanting to break the spirit of Flashback Fridays, I refer to “Why Aren’t We Insulted?” from just a few weeks ago, but this is really a slightly different subject.

On March 1 I wrote, “When companies and politicians treat us like compete idiots or pander to us by latching on to the latest trends, I think we should be insulted. We are being manipulated, but continue to respond predictably.” Equally insulting is a new trend in reporting on the coronavirus. The media treats us like fools and idiots without any pushback from readers and viewers.

I’ve heard it many times on local TV news as well as national network news, and I see it in print: “The death toll from coronavirus continues to rise.” Here are just a few quick examples from CBS, US News and the Baton Rouge Advocate.

Think about this for a minute. The death toll from anything is always going to rise unless there are zero deaths. The latest death toll, the one they refer to and display on the screen, is calculated by adding new deaths to the ones already reported. If there is only one more death, the toll goes up. And unless someone miraculously rises from the dead it will never decrease! In the middle of a pandemic, few additional deaths would be cause for some optimism. But optimistic news takes a back seat, and breathlessly reporting of “continuing to rise” is more frightening and better serves their purpose of keeping everyone in a panic, tuning in and anticipating their next breaking-news bombshell.

As critical thinkers, we should be insulted by such misleading headlines, but apparently we are not. We get the news that they want to serve up in the format they want to use and with built in bias. Journalism is, for the most part, dead. We get the news we respond to (or at least tolerate). We get the news we deserve.

They keep advertising "We are all in this together," but imagine the shock and surprise if just one reporter at the daily press conference asked the simple question, "What can we do to help?"

Understanding Experiments

When most people hear the word experiment, they picture a scientist in a lab coat with bubbling beakers and test tubes of mysterious liquids. This is not the real meaning. As a result of this misconception, news of the latest study is usually misleading.

An experiment is a rigorous process of testing an idea with the intention of either solving a problem or of improving a situation. Necessary first steps include defining the problem to be solved or determining how results will be measured. No one can claim improvement without measurements to compare (before and after). In the first case, the experiment is successful if the problem goes away. In the second, success is judged by the measurable amount of improvement.

When a well-designed experiment is successful, the implication is that the same solution can be applied widely to other situations: to solve the same problem elsewhere or to achieve the same amount of improvement. (Usually others replicate the experiment before findings are accepted.)

To achieve satisfactory results, any experiment must be well designed. Sloppy studies lead to problematic conclusions, ones that can’t be counted on to solve anything. Even the best experiments can yield bad information just based on the amount of diversity in the world and the fact that fluky things happen. 

Many experiments or studies the public is exposed to in the media relate to drugs or other remedies, and a strict procedure must be followed to ensure the conclusions are valid, otherwise the drugs or other remedies get on the market without proof that they are safe and effective.

In drug studies researchers try to choose a sufficiently large sample, because the larger the sample, the lower the chances of getting some oddball results just because you happened upon some atypical participants. A bigger sample tends to average out any unusual individual readings. 

The next step is to divide the sample into two parts that look as much alike as possible: same proportion by sex or race or education or income or background or location or any other feature that might affect the results. Sometimes this can only be done by random assignment to one group or the other. It's better if researchers have a good understanding of all the characteristics that might influence results and can make the two groups look as much alike as possible relative to those characteristics.

One group is treated – given the pill or the information or other treatment – the other, the control group, is given a fake pill (placebo) a sham treatment or left alone.

Afterward the groups are compared statistically to see if the change (hopefully an improvement) in the first group is significantly better than the change in the second. (Yes, there is often a change in the control group merely because the know they are participating in the experiment and believe the placebo is a real remedy.)

Ideally the people doing the testing are not aware of who is in which group (double-blind).

We know from the news that even these careful experiments can go wrong. Sometimes drugs are withdrawn from the market due to problems discovered only after they are released, released to a much larger sample size. That is why I have come down so hard and so often on vitamins and other dietary supplements where the law exempts them from the need for any research at all to prove safety and effectiveness. (They rely on endorsement, not proof, and use weasel words to imply effectiveness.)

Many times in the past I have also criticized experiments because they have been sloppy about their design. Sometimes they don’t define the problem until after the test is done and announce the findings with a press release. Sometimes the samples are too small due to budget constraints or laziness. Sometimes they rely on self-reporting so there is no real measurement. 

Finally businesses and educators like to say they are experimenting. In both cases it is rarely true. They don't set up two groups to compare. Then they measure by gut-feel.

Businesses are in too much of a hurry to do it right. They just try things, sometimes multiple things at the same time, so who knows which ones have a positive or negative or neutral influence on the final outcome.

In education they are still arguing about measurement. Teachers don’t want to be paid based on test scores, but haven't suggested a more acceptable criterion to measure their results. Yet school systems continue to try new methods and approaches without ever satisfying the first step – how to objectively measure real improvement.

Without understanding experiments, it’s too easy to be fooled by people who don’t know what they are doing and by people who do but are just trying to sell us a bill of goods. 

Flashback - Restaurant Menus

[Last Month I posted a flashback to “Behavior Has Consequences” from September 2011. The following month I used the regulations intended to make restaurant menus more transparent to show problems in each of the behavioral dimensions. Here, from October 2011, is “Restaurant Menus Demonstrate My Point.”]

Last time I reinforced the need for critical thinking by pointing out the dubious value of self-reporting surveys. Whether about politics or personal habits, they tend to be an inaccurate reflection of actual choices and behavior. I wonder why news agencies spend so much time on them. Here is an article from CBS that reinforces the point and gives good examples of conflicts within the other four dimensions as well. It’s about healthier menu choices in restaurants.

The report begins, “while 47 percent of Americans say they'd like restaurants to offer healthier items like salads and baked potatoes, only 23 percent tend to order those foods…” Since the information comes from different surveys, we must be careful, but the general behavior, if not the specific percentages, is confirmed by sales figures presented later in the report. Again there seems to be a significant discrepancy between what people say and how they actually behave.

As we read further, they remind us, “The government has stepped up its oversight — and influence — over the industry that it blames for America's expanding waistline.” This blatant admission that the government does not blame people for eating the wrong foods but blames the restaurant industry, leads the government to seek solutions by regulating restaurants instead of expecting personal responsibility to change behavior. When they find out this requirement of listing calories and offering more healthy choices is not working, what is their next option? How do they escalate when they don’t trust us to do the right thing? Next logical steps might be to increase threats to our personal freedom, perhaps minor at first, but where would it end? As this controlling philosophy remains predominant in the minds of government officials, they will feel justified in regulating many of our other choices.

Later the report cites efforts of a couple of restaurants to conform to the regulations. They don’t mention that in one way or another we are paying for the additional food preparation, research and reprinting of menus; but as we are strong in economic understanding, we are all aware of this. Like any other attempt to solve a behavior problem by attacking symptoms with regulations, it inevitably leads to higher costs for the public – not unlike the additional fees that came on the heels of consumer credit card protection – but it does not solve the problem. Most Americans and the government have yet to learn the main lesson of economic understanding – new regulations create added costs that are not absorbed by the business but are passed along to the customer.

Finally, why don’t people choose the healthy menu items? Examples in the report list as reasons: peer pressure and that “healthier foods also are usually among the most expensive menu items.” Both reasons relate to perspective: overly caring about the opinions of other people and not looking at the effects of today’s decisions on long-term health outcomes. 

All this effort and regulation tries to solve a problem (unhealthy eating) brought on by a behavioral problem (a failure in discipline). 

This single article, read from a behavioral standpoint, reinforces my point that weaknesses in the five key behavioral dimensions are the root cause of most of our contemporary crises, and therein lie the solutions, not in any outside programs or government interventions no matter how well intentioned.

Appropriately Skeptical

From time to time I see an ad from a local doctor promoting stem cell therapy for pain. It includes one endorsement telling how the office was so easy to work with and how the pain went away. For some time now I have been skeptical about the validity of this promotion. I thought stem cell research was not yet in the mainstream of medical practice, and I know that endorsements are not reliable evidence. It seemed suspicious, so I decided to look into it.

The promotional material on line states in part: “Stem cell therapy uses your body’s most powerful and flexible cells to promote natural regeneration in damaged joints.” It claims to be effective for a list of conditions: surgical wounds, tendon damage, severe muscle strain, arthritis, damaged cartilage, torn meniscus and many other joint and soft tissue injuries and conditions.

“The stem cells … come from your own body … a small quantity of bone marrow from your large hip bone.” (Using the recipient’s own stem cells avoids the need for FDA approval.) The on-site lab processes the harvested cells. The doctor then can “precisely inject your stem cell mixture where you need it … where they morph into new cell types” and provide “long-lasting relief” for “many [but not all] patients.”

My first stop was WebMD with a sub-headline reading: “Unproven, Risky Treatments Mislead Patients to Seek Cutting-Edge Therapy.” International Society for Stem Cell Research (ISSCR) “advises patients to seek only stem cell treatments being tested in clinical trials approved by the FDA”… or some approved smaller studies.

There is a lot of information on the site but it is summarized like this: “Every treatment has some risks. So the question comes down to whether the benefits outweigh the risks. And those studies haven't been done yet.” 

This Healthline report from about 18 months ago says that stem cell therapies are being promoted for a wide variety of conditions, but “very few of these applications have any scientific backing, [however] stem cell therapy for knees has been the subject of quite a few promising studies.” It would be a big improvement over knee replacement, but promising studies hardly qualify a procedure for routine outpatient application. They list the cost of this treatment at “approximately $3,000 to $5,000 per knee, depending largely on geographical location.” 

The FDA gives much of the same information. “Stem cell products have the potential to treat many medical conditions and diseases. But for almost all of these products, it is not yet known whether the product has any benefit—or if the product is safe to use.”

Consumer Reports chimes in with a sub-headline: “A new industry is booming. But critics worry that the treatments are ineffective and dangerous.” Here is a very brief summary: “Stem cells are special cells with the potential to repair damaged tissue and organs.” But “not all of them are possessed of equal power.” According to the current scientific consensus, the therapeutic potential of stem cells taken from fully developed tissues, adult cells, is believed to be much more limited. (Does this include marrow from hipbones? I wonder.)

That Consumer Reports piece is a long article with many warnings about the confusion in the field and the inability of regulators to keep up with the proliferation of clinics, both legitimate and otherwise.

Another reason I am skeptical is that the same doctor offers many other questionable services including platelet-rich plasma (PRP), calling it “one of the most powerful natural healing methods available today.” Some conditions include dry eyes, hair loss and erectile dysfunction.

The Pain Science website opinion published earlier this year describes it this way: “injections bathe troubled cells in a concentrated mixture made from your own blood. Hopefully this stimulates healing where it is otherwise failing … but no one really knows for sure yet.” Regardless, it’s not hard to find someone willing to do it for you, but it’s not cheap. “Without any clear evidence of benefit beyond placebo, PRP is now being marketed aggressively as a cure-all for sports injuries.”

I did this research not because I would consider going to a pain specialist unless I was referred by my primary care doctor. I did it just to show how careful we need to be to avoid spending a lot of money on dubious treatments. 

I didn't name this doctor because I'm sure there are similar ads running all over the country. I am not demonizing any doctor who may truly believe in such treatments, but it is a warning to patients everywhere. 

It is nearly always better and safer to be appropriately skeptical.

Flashback - What Are The Odds?

[I wrote this in October 2011 about how often the public is bamboozled by heartwarming stories of seemingly miraculous events. Often the storytellers are fooled as well, denying the possibility of a coincidence and attributing the occurrence to whatever higher power they believe in. This is comforting, but misguided.]

I recently ran across this article about identical twin sisters having babies on the same day in the same hospital. It reminded me of an Oprah show some years ago about a young boy and young girl who were best friends in a Russian orphanage, were adopted separately and were reunited by accident in a restaurant in Michigan. I may not have all the details right, but the details don’t matter. The point is that the audience oohed and ahhed over the seeming miracle. A story about such a coincidence always causes people to look for connections or causes and ask the question: What are the odds?  Well, let’s do some critical thinking.

The question is not about the odds of these two particular youngsters meeting again or of these two women giving birth on the same day. The question is about the odds of the producers of the Oprah Show going out and finding such an extraordinary situation or the odds of a newspaper reporting an unusual coincidence. (There have also been stories of a mother and her daughter giving birth on the same day.)

Consider that there are over 300 million people in the US doing their daily activities, including being born or adopted, having traffic accidents, going on vacation, shopping, working, dying, attending schools and sporting events and movies and concerts and restaurants, climbing mountains, skydiving and a full range of other activities. It is very likely that several unusual coincidences would arise somewhere over a period of time just by chance. If part of your job is to look for heartwarming or freakish stories, as a news agency or a television show would be, they should be relatively easy to find. Notice that we are not specifying that we find a story about twins giving birth on the same day or anything else. The requirement is only to find unusual coincidences. The odds of doing so are high.

I don’t want to be a party-pooper, rather a devil’s advocate. As you may know a devil’s advocate in Roman Catholic law was an official appointed to present arguments against a proposed candidate for sainthood. The Church saw the appropriateness and necessity for healthy skepticism and critical thinking when making important decisions. Likewise it should be appropriate and necessary for us all to exercise caution, to think things through more carefully before oohing and ahhing and assigning mysterious, psychic or supernatural causes to a surprising event. It’s especially important when we are faced with the “snake-oil” vendors trying to sell us miracle products or services (or people trying to sell us anything) by using amazing stories, fancy scientific-sounding arguments or faulty statistics.

100,000 Deaths from COVID-19!

Last Tuesday as rumors of new guidelines asking everyone to wear facemasks spread, I decided to watch the Task Force briefing. There was no such guidance at that time, but I was impressed by how the reporters never seem to listen to the speakers. Are they distracted by the opportunity to ask their prepared questions and ability to get airtime? I spent a good deal of the time telling the TV, “They just said that!”

In any case the first question was about one of the graphs projecting 100,000 to 240,000 deaths, even with full mitigation. This was a modeling result and was in no way guaranteed. No one asked about confidence in the model or how it could change. They just focused on the numbers, because they are scary numbers. The primary reason for the question appeared to be to get the president to say the number, so they could pin it on him. He handed it off to Dr. Birx to show the chart again and repeat the projection.

The next day those scary numbers were all over the news. CBS said, "The White House projects 100,000 to 240,000 Americans will die from coronavirus if ‘full mitigation’ measures are taken.” NBC called it a “dire warning” and only used the upper limit of the projection. ABC chimed in with, “Grim Trump, doctors say prepare for potential 100K to 240K deaths.” That story emphasized the president “abruptly” changing his mind when given new information – I wonder what ABC does when they get new information. 

I cite the mainstream media here, because so many editorials like to pick only on “cable news” when criticizing incomplete or slanted coverage.

Now let’s do what neither the media nor the task force made an effort to do, put it in perspective.

First, are all these incremental deaths? – Probably not. Some of the people who die from the virus would likely have died anyway, especially those in nursing homes. In addition, with so many people staying home, traffic deaths and other accidental deaths may be avoided, but all deaths will be recorded as virus-related and extraordinary.

Second, America is a land of big numbers. The government just passed a law to spend a huge amount, over $2 trillion! Each year Americans drive over 3 trillion miles, personal and commercial, and 2.8 million babies are born. It wasn’t too long ago we were stressing over news like this, “more than 130 people in the United States die of an opioid overdose every day.” And today: “School closures due to coronavirus have impacted at least 124,000 U.S. public and private schools and affected at least 55.1 million students.” The CDC considers over 107 million American adults obese. In America, charities, activists and politicians wanting to raise money, awareness or votes easily find such big numbers to elicit support. 

The CDC estimates 24,000 to 62,000 deaths from the flu this last season, and that’s with a vaccine available. In 2018, the number was 55,672 from flu and pneumonia. If we had 100,000 deaths from coronavirus in 2018 (the last year with complete numbers), it would have ranked seventh among leading causes of death just ahead of Diabetes. 

In fact the total number of deaths in the US from all causes was 2,813,503. On average over 234,000 people die every month from other causes. It’s all counted in big numbers.

Relative to some of these numbers, 100,000 across the entire population is not that large; but taken by itself it can be scary. The task force uses it without perspective to motivate people, to shock them into doing the right thing. The media piles on by using it without perspective to attract viewers and to sell newspapers.

We should be able to cooperate in the containment effort without fear and be able to stay calm knowing the media agenda is to upset us enough to ensure we buy more of what they are selling. But that's not what's happening.

Flashback – Build a Wall?

[Believe it or not, at the end of 2011, long before Donald Trump rode this issue to the White House, I wrote a piece with the title “Build a Fence.” Back then; when a Trump presidency was less than a minor consideration, many other people were talking about the need to control the southern border. Some of them later opposed the idea merely because of who was promoting it.

I also opposed a fence or wall because the issue could not be solved without changing the incentives that drive behavior. As long as illegal action yields positive consequences, it will continue. It called for better policies, and we are still waiting. Here are my thoughts from New Years Eve 2011.]

You are pushing your cart to check out at the grocery store and see ahead of you a man with his young son. The man is unloading his cart onto the conveyor and the toddler is sitting in the child seat. Suddenly the boy notices the candy along the side of the lane, lets out a scream and starts reaching. His father, distracted with the groceries and embarrassed, tries shushing the kid. Well, that just leads to more screaming and reaching. The father is at his wits end, trying to get control of two demands on his attention, the groceries and his son, while glancing around with an apologetic look to everyone in earshot. Finally, he relents and hands the child a candy bar so that he can pay for his groceries and get out of there.

What you are probably thinking at this time is: “Quiet, at last!” but also “That father is in for a real challenge because he has just reinforced a negative behavior." He rewarded the screaming and fussing and can surely expect more of the same in the future. You are also hoping you do not end up in the store at the same time as this family in the future. Don’t feel guilty. That’s exactly how most people would feel. Any right-thinking adult with an iota of life experience knows that for children, as well as for adults, behavior rewarded is behavior repeated. Behavior discouraged is behavior modified.

Now let’s look at the problem that some people refer to as illegal immigration. People sneak into the United States. They get free public education for their children. They are given jobs by employers who look the other way, just grateful to be able to get someone to do the work “that Americans refuse to do.” They get free medical care at emergency rooms. If that medical care is the delivery of a baby, their new family member automatically becomes an American citizen eligible for government benefits.

Some people who want to discourage this behavior think that the answer is to build a wall or a fence instead of recognizing what we all know: behavior rewarded is behavior repeated. Others think that the solution is to confer citizenship on those who have gotten away with it for a given number of years instead of recognizing what we all know: behavior rewarded is behavior repeated.

For some reason, logical thoughts like this can get a person branded as a racist because most of the people in that category are from one country. This is not about race or country of origin; it’s about behavior. If you don’t want a person, any person of any age, to sneak into your country (or have a temper tantrum in the grocery store), you set up a system or react in a way that discourages such behavior. You get more of what you reward and less of what you repress. 

There are already significant barriers, the hurdles of the immigration laws, that hundreds of thousands negotiate every year to come into this country legally from Mexico, India, China, Canada, Russia and all over to study, work and live free. Most proposals from all sides for dealing with this problem, if it really is a problem, don’t seem to recognize what we already know about human behavior.

[Eight years later the government is still trying to figure this out.]