consumer use or a caution label. The caution label warned consumers that the drug should be usedonly by or on prescription of a physician. At this point the decision about which drugsshould receive a caution label was largely at thediscretion of the manufacturer. In 1951, theDurham-Humphrey Amendment set forth the ba-sis for distinguishing between prescription andnonprescription drugs. The amendment speciﬁedthat three classes of drug be available by prescrip-tion: habit-forming drugs, drugs considered unsafefor use except under expert supervision because of toxicity or other potential harmful effects, anddrugs limited to prescription use only under a man-ufacturer’s new drug application.
In 1961, an Australian obstetrician, William McBride, reported an increase of fetal malforma-tions in association with the hypnotic drug thalid-omide. Although thalidomide was heavily marketedin Western Europe, approval of this drug was de-layed by the FDA in the United States and nevermade it to market. This near catastrophe, however,highlighted the need for more stringent laws, andin 1962, Congress passed the Kefauver-Harris Amendment. This act not only required that man-ufacturers prove to the FDA that a drug is safe but,for the ﬁrst time, required that the manufacturerprovide evidence that the product was effective forthe claims made in labeling.
Effectiveness neededto be established through adequate and well-con-trolled investigations by qualiﬁed researchers.In the late 1970s there was concern about thequality of scientiﬁc data submitted to the FDA. This concern led to the establishment of goodlaboratory practices and guidelines for clinical trialsto assure the quality and integrity of the safety dataﬁled with the FDA. Important elements of theguidelines included the qualiﬁcations of the inves-tigator, the study facilities, study management,safeguards for the safety and rights of patients,adherence to the research protocol, record keeping,and study monitoring. Many of these guidelineshave now become regulation, such as the need toprovide informed consent and the basic elements of informed consent, and essentially spell out the re-quirements for institutional review boards (IRBs).
In 1987, partially in response to the human im-munodeﬁciency virus (HIV) epidemic, new regula-tions were developed to accelerate approval forhigh-priority medications. Before then, drugs wereapproved based on their effect on the illness or onsurvival. Accelerated approval allowed the FDA to judge drugs using a surrogate endpoint, or theeffect of the drug on a physiologic process ormarker associated with a disease. For example,CD4 cell counts could be used to measure theeffectiveness of an antiviral medication in treatingHIV-infected patients. This new standard allowedthe FDA to approve a promising drug withoutcompleting a full clinical trial.
Drug development can generally be divided intophases. The ﬁrst is the preclinical phase, whichusually takes 3 to 4 years to complete. If successful,this phase is followed by an application to the FDA as an investigational new drug (IND). After anIND is approved, the next steps are clinical phases1, 2, and 3, which require approximately 1, 2, and 3 years, respectively, for completion (Table 1). Im-portantly, throughout this process the FDA andinvestigators leading the trials communicate witheach other so that such issues as safety are moni-tored. The manufacturer then ﬁles a new drugapplication (NDA) with the FDA for approval. This application can either be approved or rejected,or the FDA might request further study beforemaking a decision. Following acceptance, the FDA can also request that the manufacturer conductadditional postmarketing studies. Overall, this en-tire process, on average, takes between 8 to 12 years.
Figure 1 summarizes the drug approval pro-cess.It is not surprising that from conception to mar-ket most compounds face an uphill battle to be-come an approved drug. For approximately every 5,000 to 10,000 compounds that enter preclinicaltesting, only one is approved for marketing.
A 1993 report by the Congressional Ofﬁce of Tech-nology Assessment estimated the cost of developinga new drug to be $359 million.
Newer ﬁguresplace the cost at more than $500 million.
The ﬁrst step, a preclinical phase, is to ﬁnd apromising agent, which involves taking advantageof the advances made in understanding a disease,pharmacology, computer science, and chemistry.Breaking down a disease process into its compo-nents can provide clues for targeting drug develop-ment. For example, if an enzyme is determined tobe a key component of a disease process, a re-searcher might seek ways to inhibit this enzyme.
September–October 2001 Vol. 14 No. 5