Thomas A. M. Kramer, MD


Medscape General Medicine. 2002;4(3) 


In the course of my teaching, consulting, and just talking about psychopharmacology, it has become clear to me that most practitioners do not have the vaguest idea where psychotropic drugs come from. Although these clinicians may be quite knowledgeable about the positive and negative attributes, interactions with each other, and relative merits, very few have any idea about how they came into being in the first place. As such, I thought it might be helpful for the readership of this column to get a basic introduction to drug development, in order to learn something about the origin of the prescriptions that they write daily.

Drug development, until fairly recently, was at best a random, and at worst a problematic and frustrating, process. Often, medications that were developed for one thing were discovered quite accidentally to have much more important therapeutic effects for a completely different disorder. It has been well described that some of the original antipsychotics were originally developed to assist in anesthesia, and some of the original antidepressants were originally intended to be medications for tuberculosis or psychosis. Drug development was done on a "chemical" basis; that is, guesses were made as to compounds that would be safe and effective based on chemical structures of established medications. This was very much a trial-and-error process, since very little was known about how these drugs worked and very little could be measured beyond actually giving them to a patient.

Drug development always has been and always will be a partnership between efficacy (ie, whether the drug is effective) and safety (ie, whether the drug can be tolerated by a patient). There were very few ways of knowing the answers to those two questions about any given compound unless you tried it, a process not without its obvious risks. Clozapine was developed many years before researchers actually determined in any definitive way that it was effective in the treatment of schizophrenia. The reason it sat on the shelf for so long was that it was developed at a time in which the only test to see if a drug was an effective antipsychotic was to inject it into a rat, and see what happened to the rat's tail. At the time, all effective antipsychotics made a rat's tail stiff when you injected the medication. Clozapine did not make the rat's tail stiff and, thus, was felt to be an ineffective antipsychotic until it was actually tried in patients at a later time.

Drug development is somewhat more sophisticated now in that some drugs can be developed biologically. This means that instead of guessing and experimenting with various chemical structures, hoping to find something that works, we can look at what we do know about receptors and transmitters and try to design drugs around that. For example, since we have discovered that antipsychotic drugs tend to be more effective when they block both D2 and 5HT2A receptors, we can go to the laboratory and design compounds that block both of those kinds of receptors. One can only assume that as our technology improves in this regard, we can be more specific and more directed in developing new medications. Once an actual mechanism of drug action is found, multiple drugs can be developed to influence that mechanism. This can be seen with the drugs that focus their activity on the serotonin transporter, such as selective serotonin reuptake inhibitors and the newer generation of drugs in the pipeline now with peptide-based mechanisms of action, such as substance P and neurokinin inhibitors.

Regardless of how the compound is discovered, compounds are ultimately identified that have possibilities as good drugs for human beings. The Office of Research and Development of the Pharmaceutical Manufacturers Association reports that it takes an average of 12 years for an experimental drug to travel from laboratory to medicine chest. In 1993, according to a report by the Congressional Office of Technology Assessment, it took $359 million on average to get one medication from the laboratory to the pharmacist's shelf. In 2000, the cost has been estimated at $802 million. Compounds that constitute the best guesses of pharmaceutical developers start out in preclinical testing. This testing consists of laboratory and animal studies that test for biological activity of the compound against the targeted disease and various evaluations for safety. These tests take approximately 3.5 years to complete.

Approximately 1 compound out of every 1000 that enter preclinical testing actually makes it to some form of human testing. In order to do human testing, the pharmaceutical company must file what is called an IND (investigational new drug application) with the US Food and Drug Administration (FDA). The IND becomes effective if the FDA does not disapprove it within 30 days. The IND shows the results of previous experiments and how, where, and by whom the new studies on humans will be conducted. It also gives the basic information of the drug as known to date such as the chemical structure, what the drug company's best guess is as to how it will work in the body, any toxic effects found in the animal studies, and how the compound is manufactured. In addition, as is true with all research on human subjects, the IND must be reviewed and approved by the Institutional Review Boards where the studies will be conducted. Progress on the clinical trials must be submitted at least annually to the FDA.

The first set of human clinical trials for a new pharmaceutical are called phase 1 trials and usually involves 20 to 80 healthy volunteers. These tests take about a year and study a drug's safety profile, including the safe dosage range. These studies also determine how a drug is absorbed, distributed, metabolized, and excreted and its duration of action (ie, its half-life). At the end of these studies, a decision is made whether to continue to phase 2. If the compound looks like it might be a viable pharmaceutical at the end of these studies, phase 2 trials are begun. These are the first time that patients who actually have the disease the drug is supposed to treat are given the compound. In phase 2 trials, the drug's effectiveness is assessed. This usually is done with approximately 100 to 300 volunteer patients and takes about 2 years. This is also the first point at which side effects are noted and the issue of whether actual patients can tolerate the drug is first addressed. If, after the phase 2 trials, the drug still looks viable, the clinical trials go into phase 3 trials, which are the longest and largest of the clinical trial process. Phase 3 trials usually last about 3 years and involve somewhere between 1000 and 3000 patients in various clinics and hospitals at various sites. Physicians monitor patients closely to determine efficacy and identify any adverse reactions. One of the reasons these trials go on so long is that this is the first opportunity to see what effect the drug has over a relatively long period of time. For every 5 compounds that enter clinical trials, only 1 makes it through to the end.

If the drug is that 1 in 5 that actually makes it through clinical trials, the next step is to file a new drug application (NDA) with the FDA. The pharmaceutical company will only do this if it analyzes all the data and feels that the drug does demonstrate both safety and effectiveness well. The NDA must contain all of the scientific information the company has gathered. NDAs typically run approximately 100,000 pages or more. Although by law the FDA is allowed 6 months to review an NDA, in almost all cases, the period between the first submission of the NDA and final FDA approval exceeds that limit. The average NDA review time for new pharmaceutical compounds approved 10 years ago in 1992 was 29.9 months. Current data points to 12 years from the time a new chemical compound is synthesized until it is approved by the government for marketing in the United States.

Once the FDA approves the NDA, the new medicine becomes available for physicians to prescribe. The company must continue to submit periodic reports to the FDA including any cases of adverse reactions and appropriate quality control records. Sometimes the FDA requires additional studies, referred to as phase 4 because they are done after the clinical trials are complete and the medication is available to evaluate long-term effects or other issues with the medication.

Although this is a long, difficult, and expensive process, it is clearly profitable for the pharmaceutical industry, and they are increasing their efforts and budgets in this direction. The pharmaceutical industry will invest 12.6 billion dollars in research and development this year, and that investment has been doubling every 5 years.

It is important to note that these clinical trials have methodologic problems of their own. Most of these studies are randomized, placebo-controlled trials. Much has been written lately describing the rigorous inclusion and exclusion criteria for these trials and how little resemblance the patients who end up on these trials have to the kinds of patients we all see in our offices. Since these data are going to be scrutinized by the FDA, companies are very careful to do studies that the FDA will find encouraging. Since all data collected on any given compound are required to be submitted to the FDA, companies work very hard to pick the studies and the patients to make the drug look as good as possible. As much money as these clinical trials cost, the drugs can make considerable more money if they are successful, so there is a great deal at stake.

The studies that are done in clinical trials must demonstrate that the drug is safe and effective but nothing more. The idea is to test a potentially commercial product, not to find out scientific truth. Thus, the studies are not designed to gather the most or the best data; they are designed to tell the FDA what they need to know and nothing more. Issues of different pharmaceuticals being more or less effective in different kinds of patients are unable to be determined by the kind of studies that are done for drug trials. While there is much virtue in drug development in that it brings us new pharmaceuticals, it is important to note that these clinical trials are not a substitute for real scientific research done outside of the context of pharmaceutical company drug development. It is only with studies separate and apart from drug development that we will find out information about comparative treatments and the complicated, comorbid, usual patients that are actually seen in practice.