Tuesday, April 03, 2012

Drug Development and Pharmaceutical Companies: Why Are Getting New Medicines to Market so Painfully Difficult?

Mike: Hey pal, can you loan me $50?

Barry: You've caught me at a bad time, Mike. I have it. May I ask what it's for?

Mike: I need a money order for this awesome new medicinal drink they're advertising on TV. It's going to heal my chronic back pain.

Barry: Late night infomercials again?

Mike: This stuff really works!

Barry: Like the knives you tried to slice through your shoes with and the piece of ab-rolling metal that, in only five minutes a day, will turn you into Hercules?

Mike: I know it's real this time. The expert said the only reason we haven't heard about this drink is because the evil money-grubbing pharmaceutical companies are conspiring to hide this amazing product from us.

Barry: So clearly this amazing drink has undergone extensive dose-ranging safety testing and randomized double-blind placebo-controlled pivotal trials?

Mike: Of course they have! Wait…what?

Barry: Sigh. Listen to me, my shoe-less beer-bellied friend. Drug companies do get criticized for their business practices, and sometimes deservedly so. But drug development is an incredibly complex and expensive process. Before you indiscriminately write off all pharmaceutical companies as soul-less, profit-driven corporate beasts and spend your…or should I say, my hard-earned money on every snaky ointment that claims miraculous results, it would behoove you to understand a bit more about the nuances of drug development.

Mike: Hang on; I think the Giants game's about to start…

Barry: Sit! First of all, really smart scientists must study the mechanisms of a disease, be it cancer, heart disease, multiple sclerosis, anemia, and so forth. They then theorize ways to help treat the disease. For example, researchers found that the hormone estrogen was an important factor in promoting breast cancer. They also found that an enzyme called aromatase was responsible for a key step in the creation of estrogen. So if they theorized that if they can come up with a drug that would inhibit aromatase, they may reduce estrogen levels and ergo breast cancer. Then the next step is to screen for the most feasible and potentially effective drug compound to use. Researchers often screen many thousands of compounds before deciding on the best one to pursue.

Mike: Wow, that's sounds more time-consuming than my girlfriend trying to decide what shoes to wear before a date.

Barry: At least she wears shoes. So after the target compound is chosen, it goes through further extensive animal and lab testing to determine such things as what the body does to the drug (pharmacokinetics), what the drug does to the body (pharmacodynamics), and toxicity. Only after substantial answers are found in all of these areas is the drug then allowed to be tested in humans.

Mike: I once took a bottle of sleeping pills and a bottle caffeine pills together to see which one would win.

Barry: That would explain a lot. But in the post- Neanderthal era of drug development, the next steps are generally incremental phases of human testing to determine what dose level of the given drug is most ideal in terms of both efficacy and safety. The final phase before possible FDA approval is typically a blinded placebo-controlled trial involving hundreds if not thousands of patients.

Mike: Why do the patients have to be blind?

Barry: They're not blind, you ninny. A blinded trial, or more specifically, a double-blinded trial, means that neither the doctor nor patient knows whether the patient is getting the study drug or the placebo or control drug. To explain: in order for a drug candidate to get FDA approval, it must either prove that it's better than a placebo or that it's better and/or has less side effects than an existing approved treatment.

Mike: But why the blinding hassle?

Barry: I'm getting to that. Remember when your older brother gave you a glass of water and told you it was Canseco-brand steroid and growth hormone combo elixir? Remember how you swore it worked and tried to lift a Toyota?

Mike: Why do you think my back hurts?

Barry: Precisely. The placebo effect is a real phenomenon, so the FDA requires a drug candidate to demonstrate in blinded trials that patients taking the drug show statistically significant improvement versus patients taking placebo. The doctors are "blinded" as well so that, for instance, they don't knowingly or unknowingly score drug patients higher than placebo patients in their evaluations.

Mike: I guess you're right - the whole process sounds much more complicated and cumbersome than I thought.

Barry: And long and expensive. Back in 2001, a closely-watched report from Tufts University estimated that, industry wide, development costs per drug exceeded $800 million from beginning to end, and the development time for the average drug was about 12 years. My point is that very significant time, effort, and cost are put into proving that a given drug works and is safe. Public policy demands this proof. By the same token, public policy then allows drug companies to charge hefty prices for approved drugs, both to let them recoup money spend on drug development as well as provide financial incentive for future investment. Now whether some drug companies at times gouge or overcharge is a separate discussion, but clearly one can see that developing drugs isn't cheap.

Mike: So what you're telling me is if a product hasn't gone through the aforementioned extensive testing and such, it doesn't work?

Barry: I'm not saying that. I'm only saying there isn't adequate evidence that it works. The only "evidence" your back pain elixir commercial provides is a half dozen supposed elixir ingesters who profess fabulous results. Let's say for the sake of argument that these folks are not intrinsically biased because they're paid or related to the producer. How can you be sure the results aren't placebo effect? Or that they recently altered some other aspect of their lifestyle that led to the results?

Mike: Like by using this new product they constantly had to get up and pee all hours of the night, which led to increased exercise capacity and the loosening of their back tension?

Barry: Uh - okay, sure. Furthermore, we must realize the human body and its processes are quite complex. By extension, any treatment that fundamentally alters these processes often has unintended and even multiple effects.

Mike: What do you mean?

Barry: Let me give you a fairly recent example. Multiple sclerosis is a terrible disease in which one's own immune system, specifically the T-cells, attacks one's own brain and central nervous system. MS sufferers can experience anything from muscle weakness and movement impairment to blindness and paralysis. A few years ago, a drug named Tysabri discovered and marketed by Elan Pharmaceuticals (ELN) came along that seems to be a very effective treatment for MS. How does it work? Well, it does its magic by adhering to T-cells and prevents them from reaching and attacking the brain and spinal cord.

Mike: Sounds perfect!

Barry: Well yes, if not for a virus that you might have.

Mike: I was drunk, and it was my first time in Vegas…

Barry: Not that virus. I'm talking about theJCV, or John Cunningham Virus. Most people have not heard of it, but 50% or more of us humans have it. The reason you're likely not aware of JCV is for the most part it's quite harmless, because our immune systems prevent it from doing anything bad. However, should it somehow reach our brains and central nervous system, we could get a pretty nasty disease called progressive multifocal leukoencephalopathy, or PML which can be fatal.

Mike: Yeesh...you know I'm afraid of anything I can barely pronounce.

Barry: Which explains why you're nervous around giraffes and Eskimos. Anyway, because Tysabri works by controlling an MS patient's immune system so it doesn't attack the brain and central nervous system, and because that very same immune system keeps the JC virus from doing potentially bad things, it's not far-fetched to realize that MS patients taking Tysabri are at increased risk of PML. Look at it this way: think of your immune system as your strong and trusty body guard. After taking a hallucinogenic drink (say, something suggested by an infomercial), the bodyguard turns on you and begins beating you up. In response, you tie your bodyguard up good and snug so he can't hit you anymore. But this now allows all the bad guys the bodyguard was previously keeping at bay to jump you.

Mike: So Tysabri's future as a treatment is doomed?

Barry: Of course not. The risk of PML is quite small, and many thousands of Tysabri patients are doing very well on it. Besides, turns out a number of other popular drugs also increase the risk of PML in patients, and there's indication that PML risk can be better managed in the future. The main point is this: the human body and its associated functions, diseases, and so forth, are very complicated. A potent medicine that performs a positive function may also result in other unintended side effects that are not so positive. That's why massive time and effort are taken to study each proposed medicine to try to quantify its relative effectiveness and potential safety issues. In conclusion, I'm not saying your infomercial pain drink definitely doesn't work. I'm only saying that, because the product's professed efficacy isn't based on comprehensive clinical trial testing evidence but rather on the anecdotal stories of a few people who look remarkably like the infomercial producer's fraternity brothers and their relatives, there's room for skepticism.

Mike: I agree. Thanks for the talk buddy. And guess what? You can keep your $50 because my back pain seems to have gone away.

Barry: That's okay. To me, you will always be an effective pain in the butt.

Note: This article was originally published in Yahoo/Voices.


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