The other day my mother-in-law called me to say she’s been thinking about pharmaceutical development. She wondered if this might be a topic for my column. After our conversation I thought, how remarkable is the curiosity of this ninety-seven year old woman. I can only hope that I remain inquisitive through the last third of my life. Joanna would have made a good internist!
As an internist and geriatrician, I use more medication than my surgical colleagues. Actually, I’m glad we have lots of drugs. The trick is to use medication when good science supports its use, and when the benefits of therapy outweigh the risks. These days I’m struck by the number of “guidelines” promulgated by “experts.” Too often these seem to focus on the herd rather than thoughtful consideration of the individual steer. As an example, the complex decisions of vascular disease treatment cannot be reduced to an algorithm no matter how well intended. And drugs are everywhere, including the streets. I continue to be amazed by television ads and disclaimers for “little blue pills” or male hormone replacement therapy. There must be some pretty desperate folks out there willing to override government mandated disclaimers and warnings.
Before the big government types begin to howl, let me assure you that I’m not overly critical of the FDA (Food and Drug Administration). This agency is responsible for, among other things, the safety of pharmaceuticals. I’ve written favorably of the FDA in past columns. The thalidomide tragedy is an example of the benefits of our Federal watchdog. Americans were spared Europe’s heartbreak when the pregnancy-associated nausea drug, thalidomide, which caused phocomelia (seal babies), was not allowed in the US.
However, we now live in a global economy, and the lure of less expensive drugs from overseas may pose additional risks. I personally read labels and refuse to give my dog food made in China. Unfortunately, many components of the manufacturing process originate in countries with different regulations. A serious bleeding problem surfaced some years ago in patients treated with the anticoagulant heparin traced to a defective component procured from China.
Drug development begins when a chemical is conjured up in a laboratory and then registered with the US Patent Office. This intellectual property is secure for twenty years unless stolen and sold elsewhere. The recording industry is a frequent victim of intellectual property theft as pirated versions of their property is are sold on the streets of New York alongside “real” Gucci watches. And industrial espionage has been taken to a new level by internet cyber-attacks.
After the formulation and patenting process, the first stage of drug development is pre-clinical. In this stage a drug’s activity against a germ or its ability to lower cholesterol might be considered. Additional important aspects of the chemical are its metabolism and dosing, and toxicity issues in animals. If favorable results emerge, the data are sent to the FDA for review and approval before any clinical phase of testing can proceed.
You may have seen advertisements seeking participants for “clinical trials.” Phase one clinical trials are usually done in young healthy male volunteers and focus on safety and dosing issues. It’s easier to study results in a subject who doesn’t have confounding medical problems. Obviously, pregnant females are precluded to avoid harming the baby. Phase two trials look at efficacy and safety of a drug in patients with a medical problem like pneumonia. In phase three trials large numbers of patients are treated with the study drug. This often necessitates multiple clinical research sites and pooling of results. As a doctor I’ve supervised many patients in phase three clinical research protocols. I’ve also done phase four post-marketing studies after a drug has been approved by the FDA for the general public. Sometimes, it is during the after marketing experience that infrequent, but severe toxicities surface.
It’s difficult to determine the cost of discovering a drug and bringing it to market because a company’s capital costs may be co-mingled with the “out-of-pocket” costs of developing a single drug. A realistic cost of R&D (research and development) and bringing a drug to market may be one billion dollars. Furthermore, it often takes in excess of ten years to market a drug and begin to recover some of the investment costs.
The cholesterol lowering drug Lipitor and the potency agent Viagra made lots of money for Pfizer pharmaceuticals. On the other hand, a Pfizer phase three drug designed to raise HDL (the good cholesterol) resulted in several unexpected deaths and the loss of two billion dollars invested in the project. This disaster led to the layoff of thousands of workers. Clearly, it is risky business to try and pick a winner from thousands of synthesized chemicals.
I sometimes wonder how anything gets done given the complexity of life. I love Gary Larsen cartoons and one of my favorites depicts a scientist with a Sigmund Freud like beard and a white flowing lab coat standing at a chalk board covered with mathematical equations and formulas purporting to explain the origin of life. Right in the middle of all the chalkboard scribbles is a box stating “something happened” enabling the scientist to balance his equation and explain the results.
We certainly know more than we did in the past. And we are more efficient in our industries than before. Sometimes I envision our individual small efforts as ants working to drag bits of food back to support the colony. One ant seemingly does little, but together the ants mysteriously accomplish great things.
The mystery and majesty of the universe abounds for those who have eyes to see these wonders. I believe pondering mysteries is what humans were designed to do, and our pursuit of truth is worshipful. You see, all that is exists is a result of and within the Master’s Creation. It is our job to seek the magical ingredient, the “Something” in the equation we call life.