How a Drug Is Born

Big Pharma is not a misnomer. Pharmaceutical drugs are big business. The US is the world leader in producing new drugs and is  responsible for  nearly half of the new molecular entities (NME’s) that come on the market.  Americans spend well over $300 billion yearly on prescription drugs. Both Big Pharma and the FDA have come in for harsh criticism, much of it deserved. A casual observer might jump to the simplistic conclusion that they are both evil. But organizations can’t be evil, and the humans in those organizations are not evil; as with anything involving humans, there is a mixture of good and bad. Let’s review where drugs came from and how Big Pharma and the FDA develop and approve new drugs.

Ancient history

For most of human history there were no pharmaceutical companies, no pills, no drugs as such. There was only folk medicine and herbal medicine; and that’s still all that people have in some parts of the world today. People have been self-medicating with medicinal plants for at least 60,000 years, since the Paleolithic. That has always intrigued me. I wish I had a time machine and could go back to interview those who were the first to try any given plant remedy. The first users must have been either incredibly brave or incredibly foolhardy. Who was the first person to try chewing willow bark for pain? What were they thinking? How did they get the idea in the first place? How did first users decide what part of a plant to ingest and whether to try it raw or cooked or prepared as an infusion? The entire foxglove plant is toxic; how did they avoid poisoning themselves long enough to discover that the digitalis in it had medicinal value? Would you go out into the forest and eat a random plant to see what happened? By trial and error, our ancestors did somehow manage to discover some effective remedies, but it truly boggles my mind. I can’t help wondering what they were thinking and how many were harmed during the discovery process.

Modern improvements

Some people still take digitalis leaf and willow bark supplements because they see them as more “natural” than modern drugs. This makes no sense whatsoever. In the first place, “natural” doesn’t mean safe and effective. Strychnine is natural but highly poisonous. Willow bark contains salicin, which is effective for pain and fever, but only after the body converts it to salicylic acid. Chemists developed an improved synthetic drug, acetylsalicylic acid, that was less irritating to the stomach than salicylic acid; it was marketed as aspirin. Aspirin is a pure product; willow bark contains a lot of other ingredients. Aspirin provides a precise, controlled dosage; willow bark may contain varying amounts of active ingredient depending on how and when it is harvested and prepared. Seems to me it would be foolish to go back to chewing willow bark when you could take an aspirin.

The digitalis story is a great illustration of the advantages of modern drug development.  William Withering identified digitalis as the active ingredient in a folk remedy, and he tried out various preparations of various parts of the foxglove plant collected in different seasons.  He treated 156 patients and carefully documented his results. Digitalis leaf preparations came on the market but were problematic: the amount of active ingredient varied, and the effective dose was dangerously close to the toxic dose. Chemists isolated and purified the cardiac glycosides that were responsible for foxglove’s therapeutic effects. A purified glycoside went on the market as digoxin, under various brand names. Lab tests were developed to measure the serum concentration of digoxin, so today we can test whether the level of drug in the blood is in the therapeutic range. If tests show that the levels are too high, we can promptly and confidently diagnose an overdose and reverse it effectively with an antidote: Digoxin immune fab, with antigen binding fragments derived from antidigoxin antibodies produced by sheep. Since modern digoxin offers all these advantages, there is no reason for anyone to choose digitalis leaf over digoxin.

Around half of pharmaceutical drugs are derived from plants. Someone suggests that a plant might have a medicinal use, based on observations, anecdotes, or other factors. They start by identifying, isolating, and purifying the active ingredient. They make chemical modifications that improve its effectiveness and safety. And quite often they develop a synthetic version that is even better. Artemisinin, an anti-malaria drug,+- was touted as a success of traditional Chinese medicine (TCM). A Chinese researcher, Tu Youyou, won a Nobel Prize for it. But it was actually a triumph of scientific medicine. She got the idea of trying it by picking it out of hundreds of plants mentioned in TCM as useful (mainly for other purposes, not for malaria), but then she did exactly what Big Pharma does. She took a plant remedy, isolated and purified the active ingredient, developed a chemically modified preparation, dihydroartemisin, that worked ten times as well, and eventually found a synthetic version that was even better.

The Drug Development Process

Only one in 5000 drugs that look promising enough to enter preclinical testing ever make it to market, and the process can take 12 years. There are many steps in the drug development process.

Preclinical testing: Laboratory and animal studies must demonstrate the biological activity of the drug against the targeted disease, and it must be evaluated for safety.

Investigational New Drug Application (IND) A new drug application must be reviewed and approved by an Institutional Review Board (IRB).

Phase I Clinical Trials. The first test on humans is typically done on 20-80 healthy volunteers to study the pharmacokinetics: safe dosage range, absorption, metabolism, excretion, duration of action, etc.

Phase II Clinical Trials are controlled studies of effectiveness done on 100-300 patients who have the disease the drug is intended to treat.

Phase III Clinical Trials are large randomized controlled trials involving 1000 to 3000 patients in hospitals and clinics, lasting an average of 3 years. They compare the drug’s effectiveness to a control group and collect reports of side effects.

New Drug Application (NDA). The manufacturer analyzes the data from all the studies and presents it to the FDA for review of the evidence for the drug’s effectiveness and safety. An NDA has at least 100,000 pages, and review of the application typically takes 2 ½ years.

Phase IV Studies. Also known as post-marketing studies, these are organized collections of data on drugs after they have been approved by the FDA and have gone on the market. It is not unusual for new side effects to emerge as the drug is used by larger numbers of patients who are a more diverse group than those selected for the studies.

Warnings and withdrawals

By one estimate, about a third of new drugs approved between 2001 and 2010 were involved in some kind of safety event. Sometimes the manufacturers were required to include “black box” warnings to notify users of newly discovered risks. Only three drugs were withdrawn from the market. In many cases, a manufacturer voluntarily recalls a product after complaints are received and/or lawsuits are filed. In rare cases, when the manufacturer fails to take appropriate action, the FDA can issue a mandatory recall.

Can the process be shortened?

The FDA created a “fast track” and an “accelerated approval” path in an attempt to shorten the 12-year process, but some of the drugs that got quicker approval were found to have a larger number of adverse events. The FDA has to walk a fine line: if it postpones approval, patients who need the drug can’t get it; if it approves prematurely, there could be disasters like the European thalidomide epidemic of babies born with the birth defect phocomelia. By refusing FDA approval for thalidomide, Frances Kelsey saved thousands of American babies from being born with missing limbs.

Exorbitant drug prices: a serious problem

Some drug prices have become exorbitant, so much so that diabetics have died because they couldn’t afford their insulin and tried to ration it. The price of the lifesaving EpiPen inexplicably soared from $94 for a set of two auto-injectors to over $700. Skyrocketing prices have forced some patients to choose between life-saving medications and food.

I subscribe to The Medical Letter, which reviews new drugs; and I am constantly appalled by the prices, which are frequently over $100,000 and can sometimes exceed a million dollars.

The April 6, 2020 issue of The Medical Letter covered two new drugs recently approved by the FDA for the treatment of sickle cell disease, each offering only modest benefits and each costing over $120,000 for a year’s treatment. The standard treatment, hydroxyurea, is known to be more effective and costs less than $900 a year.

Big Pharma abuses

Pharmaceutical companies that used unethical marketing tactics to promote the sales of opioids are now being sued for their role in creating the opioid epidemic. Companies often game the patent system by making small modifications to their products to maintain monopolies. They have tried to prevent the development of patent-free generics. They have repeatedly put profits over patient welfare.

Some new drugs save lives and offer major benefits

New drugs have changed HIV/AIDS from a death sentence to a preventable and controllable chronic disease that doesn’t appreciably shorten life expectancy. We now have drugs that cure hepatitis C. We have vaccines to prevent cancers caused by two viruses: hepatitis B and human papillomavirus. There is now a vaccine for Ebola. 

My husband and I have really appreciated two of Big Pharma’s new drug developments. Having had two episodes of pulmonary embolus, I will have to take anticoagulants for the rest of my life. Until recently, it was a choice between daily injections into the abdomen or Coumadin pills, which required frequent blood tests and dosage adjustments to keep the blood level in a narrow range, and which required dietary restrictions and interacted with many other medications. Instead, now I just take an apixaban pill (Eliquis) twice a day.  No pain, no needles, no inconvenience, no blood tests, no dietary restrictions. My husband’s type 2 diabetes went out of control and we thought he would have to go on insulin, with all the complications that entails. Instead, his blood sugar was easily normalized with Trulicity, a once-a-week prefilled syringe with a convenient auto-injector. 

The bottom line: The FDA and Big Pharma are far from perfect, but they have accomplished a great deal of good. The process of new drug development and approval is responsible for major advances in medical treatment. Contrast the methods and successes of this real medicine with the claims of alternative medicine: no contest. 

This article was originally published as a “Reality Is the Best Medicine” column in Skeptical Inquirer.

Dr. Hall is a contributing editor to both Skeptic magazine and the Skeptical Inquirer. She is a weekly contributor to the Science-Based Medicine Blog and is one of its editors. She has also contributed to Quackwatch and to a number of other respected journals and publications. She is the author of Women Aren’t Supposed to Fly: The Memoirs of a Female Flight Surgeon and co-author of the textbook, Consumer Health: A Guide to Intelligent Decisions.

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