I am a drug molecule; I can cure and I can kill. My birth is a painful process, financially and chronologically (my gestation time now hovers around 12 years), to a point that now only very few well-to-do companies can afford to bear this pain. On an average, I now cost about $600 million to become a drug on the shelf, regardless of what I am capable of doing or what I should not doing (toxicity); it does not matter if I am a run-of-the-mill analgesic or a novel protease inhibitor to deactivate AIDS virus. The US companies alone spend over $25 billion per year to look for more prospects like myself. Such monumental costs are a result of two things: regulations and legal exposure. Since the mishaps caused by such drugs as thalidomide, the regulations enacted since 1962 now require that I go through a comprehensive testing, so thorough that when I am given to millions, the effects and toxicity ratios should not change. (You see, all of us are toxic because we are mostly foreign to the body; it is when what good we can do supercedes over what we should not be doing that we become an acceptable risk). The drug companies which work on me are cognizant of this fact but what forces them to pay heed to these regulations is their legal liability; one death, one new side effect can wipe me out of the market and if not properly documented with a trail of diligent studies to show that this outcome was out of question, the entire company in no time.

My discovery begins in many different ways. Most drug companies have scientists sitting in their cluttered suites thinking about how I should look like; the so called drug-modeling approach and then go out and construct me out of simpler chemical entities. The new breed of combinatorial chemists work on a mass-scale approach of studying various permutations and combinations of chemical components. Armed with robotic controls and gigabyte churning ROM’s, they can now synthesize a large number of my look-alikes in a much shorter time. It is no longer a news for a company to synthesize 100,000 of possible hits in a year and screen them out for probable activity.

More traditionally, the scientists revert to the age-old proverbial indications: the herbal source. Given the long successful history of finding new brethren of mine such as aspirin, quinine, reserpine in the roots and leaves of trees, this route seems promising. Unfortunately, the focus of drug companies to isolate identifiable entities from the natural sources often defeats the purpose of natural medicine. If you believe in the adage that Nature provided cure where it inflicted disease, we ought to be able to find cure for everything in sources natural. Regretfully, however, the concept of utilizing whole extracts of plants to cure disease, though quite popular in the Third World, has had little inroad in the West. This is a result of economic factors rather than to any aversion of the West to adopt the traditional medicine. Drug companies must secure a patent on my life to justify the millions they must spent to raise me into a full grown product on the shelf; without intellectual property right coverage, I will never see the light of the day. Secondly, if drug companies promote unidentifiable components, they will find it difficult to predict its response because the composition of the product may not be consistent, as is the case with most plant sources. Thus, if a drug company can not recoup its investment and additionally face a serious risk of liability, why should it promote a holistic approach to medicine? It is just bad business. So, we return back to the drawing board.

I am brought to life also by various fermentation processes or bacterial sources, particularly now with the advent of genetic engineering. Biotechnology has opened a new vista to look for my variants and when found; the bacteria like E Coli provide an ideal turf to grow me into a crop. The newest and the most promising of my types are now found in proteins, particularly small proteins. It is believed that most recurring diseases are a result of genetic defects and proteins can avert the effect of many of these disorders; as a result, a new field of study has opened up: small protein science with its own experts, both as analytical chemists and drug designers. Having found probable structure, companies begin to understand how and why to work. Though direct testing on animals is still the primary method, several newer techniques have become available including cell culture and in-vitro drug-receptor interactions.

The US Food and Drug Administration (US FDA), the grand dad of all regulatory authorities, makes it easy for all to know what to do; it’s doing what the FDA wants you to do that is tedious and cumbersome. First, I must be fully characterized, physically, chemically with such attestations as infra-red spectra, mass spectra, crystallographic structure, solubility, stability and host of other tests that take about 6-9 months to complete; having characterized me fully, companies repeat pharmacological screening (the first screening is often done on less pure compound) to find out if I have retained the activity I am supposed to have. Now begins the cycle of toxicology testing: teratogenicity and carcinogenicity are the main tests besides the LD50 test or how much of me it takes to kill half the animals. Having satisfied with the toxicity profile in animals (three species), and armed with detailed pharmacokinetic profile, researcher now begin their planning to put me into humans; however to do so, they need a dosage form. The dosage form development therefore begins simultaneously with my toxicity potential testing to cut time short but it is an expensive exercise. At this stage the companies file with the US FDA, an IND application: Investigational New Drug Application (INDA) requesting permission to test it for the first time in humans; the FDA grants this approval on the basis of the relative weighting of the efficacy potential versus observed toxicity in animals. This is a critical judgement for two reasons: there is no guarantee that the observed toxicity in the animals will be replicated in man. Fact is that there is no perfect model to simulate toxicity to humans—it is a risky matter. Secondly, the FDA judges the potential of efficacy. If it is a treatment of cancer or AIDS they will tolerate a greater toxicity because the diseases can be fatal themselves; however, if you were to devise a simple analgesic, you better make it very safe before they will approve it. (Some say that if aspirin were discovered today, FDA will reject it for use as an analgesic). With an approved IND, the drug companies now place this drug in humans at lower doses, mainly to observe any overt symptoms of toxicity and to evaluate in detail the pharmacokinetics of the drug. This study may utilize 10-20 healthy subjects; these data are then resubmitted to the FDA as NDA or New Drug Application, following approval of which the drug testing begins for its clinical efficacy trials at different doses and to different populations under strict supervision. A successful study may require a few thousand patients with the involvement of several study centers across the country to collect sufficient data. It is not unusual to have 100,000 patients before the data are submitted to the FDA for the approval of the drug. This approval, when received, is hailed as the major victory for the Drug Company and quickly reflects in its share price, both upwards or downward as the case may be with the FDA approval. Now I emerge as a new drug, beating the odds of approximately 1:1,000 of the proven efficacious compounds among the "good-leads". Some say, the odds are worse than winning on roulette wheel in Las Vegas; but people do win there too.

That was a quick run down on how the companies run me down; the real story begins now. How I work, how I cure a disease and how I can kill these stories are thrillers worth Ian Fleming’s novel subject.

My journey from the identification as a new chemical entity worth something to the product on the shelf takes a detailed study of how I work, not only in the body but also in the dosage form. Investigations on me begin with knowing which end of me is straight (crystal-wise) all in an attempt to determine if I will like water or not: hydrophobicity; because, if I do not like water, I will not dissolve and thus would have difficulty crossing the many biological frontiers I must go through to reach the site of action. It is also studied whether I have the prowess to withstand the hostile environment of the human body; an environment that will dissolve an ingot of iron is the one I must survive traversing from the stomach to intestine, from where I will likely be absorbed. If the scientists could not find an environment that will be friendly for me to survive, I die prematurely; there are scores of very potent drugs that will never see the light of the store shelf mainly because they are so unstable and because a proper dosage form can not be designed for them. So, the discovery of a new activity is only half the battle, getting it to work in the body is equally challenging and often more disappointing.

Having placed me in a dosage form, the journey begins where first the body gets a chance to work on me before I can show my talents. If I am a solid dosage form (tablets, capsule, etc), which mostly is the case, then first I must come out of my environs into the environs of the body fluids; it is at this stage that a lot of problems in the bioavailability are encountered because if I do not come out quickly and completely, the dosage form will pass down the intestinal column to areas where even if I come out, I will not be to go any further because this may not be the ideal absorption surface. Dosage form design therefore becomes a crucial part of my utility. And this is the reason why studies on determining drug activity must involve the design of dosage forms also. After coming out of the dosage form, I face a formidable task of avoiding many hijackers en route: mucin, binders of other kind and so on that will entrap me for long enough to push we down the canal to a area from where I can not be absorbed; I may also be deactivated chemically at this stage. This is also the time when I must demonstrate my ability to like both the water and oil since I must pass through two barriers; if I like one over other, few of us guys would get over the barrier.

Now I have through a miracle, and often in a quantity ranging from 10-70%, reached the blood circulation which must now first pass through the organ of destruction: liver. This is the first test of survival I must demonstrate. Liver is there to keep guys like myself out of the system and thus immediately begins to knock me down; the key is to lose as few soldiers here as possible. Often I am totally converted to another form, the active drug moiety, if I am to remain effective. Crossing the liver, now I face another scenario: how to sail through the blood vessels; I often have the option of tagging along to the protein molecules: plasma proteins. This is a double-edge sword. If can tag along and develop a love affair with proteins then I will not go any farther where I am needed; binding to proteins also helps me stay in the body longer. Anyway the bathing of plasma to tissues allows me to enter strange valleys through many unique barriers: blood: brain, CSF, tissue etc. Finally, a few of us get to reach where we are needed: the site of action. The irony is that few scientists know where we actually work. Often they adduce a theory and it seems plausible but the full facts are rarely known because of the interconnectivity of the activity across various sites; I may work on the brain while my main job is to kill the bacteria in the tissue; my activity in the brain might be helping to boost the immunity; Nevertheless, it is often not the number that is important (look at how one out of 12 million sperms kicks the process of procreation). What is important is that I should be allowed to stay where I am needed for long enough time to finish the job. And that is the job of a pharmacokineticist to evaluate and often modify my character to give me the lease to stay long enough to be effective.

I come to help but then like all other good armies I must also leave the body when the job is over. The human body is a true marvel of nature; it has many weapon systems ready to destroy me and often I leave through kidneys; often I re-circulate and end up in the intestine or other body tissues; but eventually, I am knocked out; some of us are truly hardy and stick around for years in the body specially when we develop affection to proteins. My exit from the body is measured by many mathematical techniques and many parameters are assigned to me; what makes it easy is the fact that I get knocked out on the simple basis of statistics. If there are more of us, more of us die, if there are fewer, few die: this forms the basis of what the scientists call the first order.

That’s a brief history of my sojourn through the human body. Who says life isn’t tough.