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From Idea to Market

From Idea to Market

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Published by: victorcc on Nov 21, 2011
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From Idea to Market: The Drug Approval Process
Martin S. Lipsky, MD, and Lisa K. Sharp, PhD 
Each year many new prescription drugs are approved by the Food and Drug Administra- tion (FDA). The process of developing and bringing new drugs to market is important for primary care physicians to understand.
We describe the drug development process based on a review of the literature and Websites addressing FDA processes and policies.
The process starts with preclinical testing. For drugs that appear safe, an investigationalnew drug application is filed with the FDA. If approved, clinical trials begin with phase 1 studies that focus on safety and pharmacology. Phase 2 studies examine the effectiveness of the compound. Phase 3is the final step before submitting a new drug application (NDA) to the FDA. An NDA contains all theinformation obtained during all phases of testing. Phase 4 studies, or postmarketing studies, are con-ducted after a product is approved. Recent changes in legislation have streamlined the approval pro-cess. Critics contend that these changes have compromised public safety, resulting in the need to recallseveral products from the market. Proponents claim that changes in the approval process help patients with debilitating diseases, such as acquired immunodeficiency syndrome, that were previously denied critical medication because of bureaucratic regulations. (J Am Board Fam Pract 2001;14:362–7.)
 The Food and Drug Administration (FDA) is re-sponsible for assuring that foods and cosmetics aresafe and that medicines and medical devices areboth safe and effective. To carry out this responsi-bility, the FDA monitors more than $1 trillion worth of products, representing about $0.25 of ev-ery $1.00 spent annually by American consumers.
Balancing the efficacy and safety of these productsis the core public health protection duty of theFDA. This mission requires examining efficacy asdetermined from well-controlled trials, effective-ness as determined from actual use in uncontrolledsettings, and safety for both prescription and over-the-counter pharmaceuticals before approving amedication for market. During the past decadealone, more than 500 new prescription drugs havebeen approved by the FDA.Physicians face the continual challenge of learn-ing about new products approved by the FDA. Theprocess of developing new drugs and bringing newdrugs to market has important practice implica-tions yet is poorly understood by most primary carephysicians. Understanding how clinical trials areconducted is important when physicians considerthe use of a new medication for patients in theirown practices. For example, the medical literatureor a pharmaceutical representative might refer to aphase 3 or phase 4 study. Table 1 provides a brief description of these terms and others used through-out this article. Understanding these terms willhelp the physician understand the risks involved inusing a new medicine and the role of clinical trialsin evaluating safety and effectiveness. Primary carephysicians who might receive invitations to partic-ipate in clinical trials need to understand the risksinvolved for patients and the importance such in- vestigations play in determining efficacy and safety issues of newly released medications. Finally, phy-sicians who challenge the cost of new medicationsmight benefit from a more complete understandingof the time, cost, and complex issues involved inhaving a new product approved by the FDA. The purpose of this article is to present a conciseoverview of the drug approval process. It willbriefly review the history of the FDA and followthe journey of a new product from early develop-ment until approval by the FDA for prescriptionuse.
 We describe the drug development process basedon a review of the literature and Web sites address-ing FDA processes and policies. Key words used forthe searches included “Food and Drug Administra-
Submitted, revised, 18 January 2001.From the Department of Family Medicine (MSL, LKS),Northwestern University Medical School, Chicago. Addressreprint requests to Martin S. Lipsky, MD, Department of Family Medicine, Morton 1–658, 303 East Chicago Ave,Chicago, IL 60611.
September–October 2001 Vol. 14 No. 5
tion,” “drug development,” and “drug approval.” The databases searched were MEDLINE andCINAHL. Also, Web sites were sought using theLycos search engine, and “Food and Drug Admin-istration” and “drug approval” as key words.
FDA: A Historical Perspective
 Misfortune, disaster, and tragedy have triggeredmost of the advances in drug regulation. At the turnof the 19th century, the marketing of medicines was not controlled, and corruption, exploitation,and fraud were rampant. Public disclosures aboutthe unsanitary conditions in meat-packing plantsand concerns about worthless or even dangerousmedicines led to the enactment of the Food andDrug Administration Act of 1906. This law (1)required that drugs meet official standards of strength and purity, (2) defined the terms
, and (3) prohibited the ship-ment for sale of misbranded and adulterated foods,drinks, and drugs.
 The FDA gained little power from this legisla-tion, and it did not prevent the accidental deaths of 107 persons in 1937 from the patent medicine mar-keted as “elixir sulfanilamide.” A well-intentionedchemist used diethylene glycol as a solvent to makea liquid formulation of sulfanilamide that would beeasier for children to take. Although the toxicity of diethylene glycol was known at the time, the man-ufacturer was not aware of it.
Existing law did notrequire that manufacturers demonstrate a drug’ssafety, and 240 gallons of the elixir were releasedinto the marketplace. As a consequence of this event, Congress en-acted the Federal Food, Drug and Cosmetic Act of 1938, marking the birth of the modern FDA. Thenew act required that a manufacturer (not theFDA) prove the safety of a drug before it could bemarketed, authorized factory inspections, and es-tablished penalties for fraudulent claims and mis-leading labels. Following the 1938 Act, the FDA began to distribute public notices (known as tradecorrespondences) to the industry regarding the la-beling and dispensing of drugs. It was in thesepublic notices that the FDA first distinguishedmedications that should be available only by pre-scription.
Specifically it required that all drugseither carry a label with adequate information for
 Table 1. Terms and De
nitions Relating to the New Drug Development Process.
 Term DenitionClinical evaluation, phase 1 Examines the pharmacologic actions and safe dosage range of a drug; howit is absorbed, distributed, metabolized, and excreted; and its durationof actionClinical evaluation, phase 2 Controlled studies in volunteers to assess the effectiveness of a drug.Simultaneous animal and human studies can continue to examinefurther the safety of the drugClinical evaluation, phase 3 Testing using a greater number of volunteer patients. The drug isadministered by practicing physicians to those suffering from thecondition the drug is intended to treat. These studies must confirmearlier efficacy studies and determine low-incidence adverse reactionsClinical evaluation, phase 4 Studies conducted after FDA approval, during general use of the drug by medical practitioners. Also referred to as postmarketing studiesFast-track drugs Fast-track approval provided for drugs that meet unmet medical needs forpatients with serious or life-threatening conditionsLabeling Any information distributed about a drug by the manufacturer, even if itis not physically affixed to the product. In addition to package inserts,labeling includes such material as advertising Misbranding Anything in labeling that is false or misleading in any particularrendersthe product misbranded, making it subject to FDA regulatory actionFDA - Food and Drug Administration.
 The Drug Approval Process 363
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 
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

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