Gettysburg Medical News
 The Clinical View
 by P.E. Hoffsten, M.D.
 9 February 2005

HOW A MEDICINE COMES TO MARKET

            In my 45 years of experience in the profession of medicine, I can’t remember a time when there was as much controversy and suspicion about medications as there is now.  It would be difficult to pick up a newspaper or a magazine without finding some article in it condemning some medication, while at the same time railing about the cost.  Pharmaceutical companies are accused of price gouging.  Our FDA is accused of being in their pockets letting drugs come onto the market without adequate research.  Alternatively, the FDA is accused of being too stringent and not letting meritorious medications onto the market.  Lawsuits against drug companies and physicians have reached the point were the price of all healthcare services are increased just to cover the premiums, let alone the settlements from malpractice problems.

            In this column, I want to review the process of how a drug comes to the market and the really amazing safeguards that are instituted before a drug ever is allowed to be sold to the public.

            The first step in development of a new drug is to identify a medical need.  A good example of a medical need is the problem of high blood cholesterol.  In the 1950’s, it was learned that a high blood cholesterol was associated with an increased rate of heart attack and stroke.  It had been known for some length of time that cholesterol deposits in arteries were associated with atherosclerotic disease.  Thus, it became an identified medical problem that high blood cholesterol be reversed.  The first and most obvious step in this endeavor was to encourage a low cholesterol diet.  As anyone who has ever tried it knows, this just doesn’t work.  Trying to get blood cholesterol down through dietary means is disappointingly unsuccessful.  The reason for this was soon discovered, when it was recognized the body produces 1200 mg of cholesterol all by itself.  On the average, we eat about 300 mg per day.  If our diet gets to 200 mg a day of cholesterol it tastes like cardboard and people simply won’t do that.  Simply decreasing the body’s daily cholesterol load from 1500 mg a day to 1400 mg a day is not at all effective. The body will simply pick up the difference and make more cholesterol when the dietary need is not satisfied.  Thus, diets for cholesterol really just don’t work.

            Research done by pharmaceutical companies actually demonstrated that there was a chemical system in liver cells that produced cholesterol.  Very logically, if the rate of cholesterol production could be decreased perhaps blood cholesterols would come down.  A drug called lovastatin (Mevacor) was found to cut the liver’s production of cholesterol in half.  This drug then entered the drug-approval process.

            Phase I of the drug-approval process requires that the drug be administered to a limited number of healthy normal volunteers (often paid for the participation) to see if the drug is safe.  At this time in Phase I, the question has to do with side effects of the medication and potential toxicities.  Generally, a hundred people are tested and hundreds of laboratory tests are done on each person to see if anything abnormal can be found.  If abnormalities are found at this stage, the drug is flushed out the system and further testing is abandoned.  On the average of 5000 different medications and chemicals that are tested, prior to ever being used in humans, only 1 in 1000 chemicals ever enter human testing.

            Phase II of the testing process involves seeking out individuals with the disease process to be targeted and see if the drug will have a favorable effect on the disease process.  Generally, Phase II testing involves 100-300 individuals again with very careful measurements of multiple different blood tests and clinical perimeters.  If the drug is found to be effective and also safe, after testing about 300 people, the drug will then enter Phase III testing.

            In Phase III testing, the drug is administered to several thousand individuals who have a disease process in question. The medication is administered to measure effectiveness and safety in this larger number of people.  This phase in testing generally requires about three years.

            Finally, after all three phases are favorably traversed, the drug information is forwarded to the Food and Drug Administration (FDA) for review and approval if the drug is going to be brought to the market.  For every five drugs that are submitted to the FDA, only one gets approved on the average.  The review process, on average, takes 2 ½ years.  Thus, going from free clinical testing to Phase I to Phase II to Phase III and finally FDA approva,l almost twelve years of experience with the medication has been obtained.

            Finally, after all of this testing has been done, Mevacor was brought to the market in 1988.  It was known that some people got slight abnormalities of liver function.  It was also known that some individuals had some muscle aching that came with the drug.  These were listed as the two major side effects.  Warnings to physician and patients were mentioned in regard to this new drug as it came on the market.

            As a drug comes on the market, pharmaceutical companies are required to do what is called post-marketing surveillance.  This means that after the drug is being sold to the public and millions of people are being treated, side-effect profiles and effectiveness profiles need to be reviewed to insure that the drug is performing in the general public.  Indeed for lovastatin, the drug did perform with the general public as it had in the original test. The patent lifespan is now expired and is available generically. The patent lifespan of a medication allows a drug company to be the exclusive producer of that drug for a period of 15-17 years, so that the drug company can recover the costs of the drug development.  On the average, bringing a new drug to the market costs100 million dollars.  One can understand why new medications on patent are so expensive when a drug company has already spent 100 million dollars for a drug that hasn’t sold one pill yet.

            In the case of Mevacor, the drug was originally brought to market with the claim that it would lower the blood cholesterol.  However it wasn’t until 2-3 years later and multiple other studies, that it was demonstrated that the drug would do the thing that you want the most.  Simply lowering your cholesterol is a number on a piece of paper but stopping heart attacks is something very real.  In the period of post-marketing surveillance, additional studies were done demonstrating that not only did lovastatin lower the blood cholesterol, it also decreased the rate of heart attack and stroke in the general public, and therefore fulfilled its original charge.

            Drugs such as Vioxx, which was recently taken off the market in the post-marketing surveillance time, makes splashy headlines.  In fact, the Merck pharmaceutical company had done all of the above testing mentioned and there was no demonstrated increased incidence of heart attack in the studies done.  Eventually, as post-marketing studies were done, the heart attack problem was uncovered and the drug withdrawn from the market.  Hardly, does this warrant a loss of confidence in the FDA or the Merck pharmaceutical company.  Rather it is a measure of success that continued monitoring of your medications by the FDA and by the pharmaceutical company leads to additional information only available after millions had been tested.  When the abnormality is discovered, the drug is taken from the market as Vioxx was.  To my thinking, Vioxx was a very effective medication for alleviating pain of arthritis and other minor ailments.  Yes, there was a slight increased risk of heart attacks using Vioxx but there is a definite risk in automobile accidents when people drive, yet we still drive.  We haven’t outlawed cars.  To me, it seems that there needs to be some understanding that no medication is going to be completely side-effect free. Risks and benefits must be weighed against each other when a medication is used.  But rather than lose confidence in our FDA and our drug company surveillance programs, I feel that they both deserve a vote of confidence and thank yous for the care and efforts that they put into bringing the drug to market.