After Drug Approval

Phase IV begins after drug approval. Once rare, there are now commonly required therapeutic use studies that go beyond the prior demonstration of the drug s safety, efficacy and dose definition. 

Studies in Phase IV are all studies (other than routine surveillance) performed after drug approval and related to the approved indication. They are studies that were not considered necessary for approval but are often important for optimizing the drug s use. They may be of any type but should have valid scientific objectives. Commonly conducted studies include additional drug-drug interaction, dose-response or safety studies, and studies designed to support use under the approved indication, for instance, mortality/morbidity studies, epidemiological studies. 

To date, clozapine remains the only drug with proven and superior efficacy in treatment-resistant patients, and it is currently the only drug approved for the treatment-resistant schizophrenic. Studies have shown a response of approximately 30% to 50% in these well-defined treatment-resistant patients. Clinical trials have consistently found clozapine to be superior to traditional antipsychotics for treatment-refractory patients, and it is efficacious even after nonresponse to other SGAs and in partially responsive patients. It is often rapidly effective even in those who have had a poor response to other medication for years. Recent studies have demonstrated that it has a beneficial effect for aggression and suicidality, which led to the Food and Drug Administration (FDA) approval for the treatment of suicidal behavior in people with psychosis.41... 

After the approval of the first product, recombinant insulin, in 1982, progress in the development of new recombinant protein pharmaceuticals was slow ([10], Fig. 17.1). The number of biotechnology-derived drugs and vaccines approved by the US Food and Dmg Administration (FDA) has increased significantly only since 1995. More recently, sales of biologies have skyrocketed, e.g. from 900 million in 1999 to an estimated 3.5 billion in 2001 for monoclonal antibodies [11]. The annual global market for biopharmaceuticals is estimated to have increased from 12 billion US to 30 billion US in 2003 [12]. 500 candidate biopharmaceuticals are undergoing clinical evaluation and over one hundred protein-based therapeutics are in the... 

Development of an Application Unrelated to Original Approved Use. After initial approval, drug development may continue with studies of new or modified indications, new dosage regimens, new routes of administration or additional patient populations. If a new dose, formulation, or combination is studied, additional human pharmacology studies may be indicated, necessitating a new development plan. 

With an approved IND, the drug company can place me in humans at lower doses, mainly to observe any overt symptoms of toxicity and to evaluate my PK characteristics, and the study may use 10 to 20 healthy subjects. These data are then resubmitted to FDA (Phase 1). After my Phase I is completed, drug testing begins for my clinical efficacy, with trials at different doses and given to different populations under strict supervision. A successful study may require a few thousand patients and the involvement of several study centers across the country (or perhaps across the world) to collect extensive data. It is not unusual to have 100,000 patients take me before the data are submitted to the FDA for drug approval — the so-called marketing approval. 

Sucrose Esters. Sucrose esters have industrial interest in the area of surfactants, " bleaching boosters, cosmetics, and fat substitutes. Synthetically prepared octa-fatty acid esters of sucrose have similar properties as the normal triglycerides, yet are not degraded by Upases, which entailed their marketing as noncaloric fat substitutes—after being approved by the U.S. Food and Drug Administration under the name Olestra or Clean . ... 

The FDA did establish, however, a procedure to determine the effectiveness of all drugs approved prior to 1962, and it established a policy of permitting the approval of a generic equivalent to a safe and effective pre-1962 brand-name drug. This generic approval procedure, however, did not apply to drugs approved after 1962. Id. 

For 15 of the 29 drug products where the brand-name company did not sue the first generic applicant, the generic applicant began commercial marketing soon after FDA approval and prior to patent expiration. In 6 cases, the FDA has not approved the generic applicant s ANDA as of June 1, 2002, and the patents have not yet expired. 

By the mid-1990s, after two decades of attention, the drug lag had been eliminated indeed, the pendulum had swung clearly in favour of the FDA. Whether due to the PDUFA resources, to the advent of more bureaucracy overseas (e.g. the formation of the European Union s central drug approval authority) or to criticism of delays at the agency, today the United States is often the first country to approve new drugs. 

Kaitin K, Cairns C. The new drug approvals of 1999, 2000, and 2001 drug development trends a decade after passage of the prescription Drug User Pee Act of 1992. Drug Information Journal 2003 4 357-71. 

The dearth of information on the metabolism of bupropion may initially seem surprising however, this drug is one of the oldest of the newer antidepressants, having entered clinical trials in the mid-1970 s and having been approved before fluoxetine ( 308, 314, 315). Ironically, its marketing was delayed after its approval because of the risk of seizures, which, in turn, is almost undoubtedly a consequence of its complicated pharmacokinetics ( 163). 

---