From Idea to Market: The Drug Approval Process
`
`Martin S. Lipsky, MD, and Lisa K. Sharp, PhD
`
`Background: 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.
`Methods: We describe the drug development process based on a review of the literature and Web
`sites addressing FDA processes and policies.
`Results: The process starts with preclinical testing. For drugs that appear safe, an investigational
`new 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 3
`is the final step before submitting a new drug application (NDA) to the FDA. An NDA contains all the
`information 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 recall
`several 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 are
`safe and that medicines and medical devices are
`both 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.1
`Balancing the efficacy and safety of these products
`is the core public health protection duty of the
`FDA. This mission requires examining efficacy as
`determined from well-controlled trials, effective-
`ness as determined from actual use in uncontrolled
`settings, and safety for both prescription and over-
`the-counter pharmaceuticals before approving a
`medication for market. During the past decade
`alone, more than 500 new prescription drugs have
`been approved by the FDA.
`Physicians face the continual challenge of learn-
`ing about new products approved by the FDA. The
`process of developing new drugs and bringing new
`drugs to market has important practice implica-
`tions yet is poorly understood by most primary care
`physicians. Understanding how clinical trials are
`conducted is important when physicians consider
`
`the use of a new medication for patients in their
`own practices. For example, the medical literature
`or a pharmaceutical representative might refer to a
`phase 3 or phase 4 study. Table 1 provides a brief
`description of these terms and others used through-
`out this article. Understanding these terms will
`help the physician understand the risks involved in
`using a new medicine and the role of clinical trials
`in evaluating safety and effectiveness. Primary care
`physicians who might receive invitations to partic-
`ipate in clinical trials need to understand the risks
`involved 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 medications
`might benefit from a more complete understanding
`of the time, cost, and complex issues involved in
`having a new product approved by the FDA.
`The purpose of this article is to present a concise
`overview of the drug approval process. It will
`briefly review the history of the FDA and follow
`the journey of a new product from early develop-
`ment until approval by the FDA for prescription
`use.
`
`Submitted, revised, 18 January 2001.
`From the Department of Family Medicine (MSL, LKS),
`Northwestern University Medical School, Chicago. Address
`reprint requests to Martin S. Lipsky, MD, Department of
`Family Medicine, Morton 1– 658, 303 East Chicago Ave,
`Chicago, IL 60611.
`
`Methds
`We describe the drug development process based
`on a review of the literature and Web sites address-
`ing FDA processes and policies. Key words used for
`the searches included “Food and Drug Administra-
`
`362 JABFP September–October 2001 Vol. 14 No. 5
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`Table 1. Terms and Definitions Relating to the New Drug Development Process.
`
`Term
`
`Clinical evaluation, phase 1
`
`Clinical evaluation, phase 2
`
`Clinical evaluation, phase 3
`
`Definition
`
`Examines the pharmacologic actions and safe dosage range of a drug; how
`it is absorbed, distributed, metabolized, and excreted; and its duration
`of action
`
`Controlled studies in volunteers to assess the effectiveness of a drug.
`Simultaneous animal and human studies can continue to examine
`further the safety of the drug
`
`Testing using a greater number of volunteer patients. The drug is
`administered by practicing physicians to those suffering from the
`condition the drug is intended to treat. These studies must confirm
`earlier efficacy studies and determine low-incidence adverse reactions
`
`Clinical evaluation, phase 4
`
`Studies conducted after FDA approval, during general use of the drug by
`medical practitioners. Also referred to as postmarketing studies
`
`Fast-track drugs
`
`Labeling
`
`Misbranding
`
`FDA - Food and Drug Administration.
`
`Fast-track approval provided for drugs that meet unmet medical needs for
`patients with serious or life-threatening conditions
`
`Any information distributed about a drug by the manufacturer, even if it
`is not physically affixed to the product. In addition to package inserts,
`labeling includes such material as advertising
`
`Anything in labeling that is “false or misleading in any particular” renders
`the product misbranded, making it subject to FDA regulatory action
`
`tion,” “drug development,” and “drug approval.”
`The databases searched were MEDLINE and
`CINAHL. Also, Web sites were sought using the
`Lycos search engine, and “Food and Drug Admin-
`istration” and “drug approval” as key words.
`
`FDA: A Historical Perspective
`Misfortune, disaster, and tragedy have triggered
`most of the advances in drug regulation. At the turn
`of the 19th century, the marketing of medicines
`was not controlled, and corruption, exploitation,
`and fraud were rampant. Public disclosures about
`the unsanitary conditions in meat-packing plants
`and concerns about worthless or even dangerous
`medicines led to the enactment of the Food and
`Drug Administration Act of 1906. This law (1)
`required that drugs meet official standards of
`strength and purity, (2) defined the terms adulter-
`ated and misbranded, and (3) prohibited the ship-
`ment for sale of misbranded and adulterated foods,
`drinks, and drugs.2– 4
`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-intentioned
`chemist used diethylene glycol as a solvent to make
`a liquid formulation of sulfanilamide that would be
`easier for children to take. Although the toxicity of
`diethylene glycol was known at the time, the man-
`ufacturer was not aware of it.5 Existing law did not
`require that manufacturers demonstrate a drug’s
`safety, and 240 gallons of the elixir were released
`into 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. The
`new act required that a manufacturer (not the
`FDA) prove the safety of a drug before it could be
`marketed, 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 trade
`correspondences) to the industry regarding the la-
`beling and dispensing of drugs. It was in these
`public notices that the FDA first distinguished
`medications that should be available only by pre-
`scription.3 Specifically it required that all drugs
`either carry a label with adequate information for
`
`The Drug Approval Process 363
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`consumer use or a caution label. The caution label
`warned consumers that the drug should be used
`only by or on prescription of a physician.
`At this point the decision about which drugs
`should receive a caution label was largely at the
`discretion of
`the manufacturer.
`In 1951,
`the
`Durham-Humphrey Amendment set forth the ba-
`sis for distinguishing between prescription and
`nonprescription drugs. The amendment specified
`that three classes of drug be available by prescrip-
`tion: habit-forming drugs, drugs considered unsafe
`for use except under expert supervision because of
`toxicity or other potential harmful effects, and
`drugs limited to prescription use only under a man-
`ufacturer’s new drug application.4
`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 marketed
`in Western Europe, approval of this drug was de-
`layed by the FDA in the United States and never
`made it to market. This near catastrophe, however,
`highlighted the need for more stringent laws, and
`in 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 manufacturer
`provide evidence that the product was effective for
`the claims made in labeling.6 Effectiveness needed
`to be established through adequate and well-con-
`trolled investigations by qualified researchers.
`In the late 1970s there was concern about the
`quality of scientific data submitted to the FDA.
`This concern led to the establishment of good
`laboratory practices and guidelines for clinical trials
`to assure the quality and integrity of the safety data
`filed with the FDA. Important elements of the
`guidelines 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 guidelines
`have now become regulation, such as the need to
`provide informed consent and the basic elements of
`informed consent, and essentially spell out the re-
`quirements for institutional review boards (IRBs).7
`In 1987, partially in response to the human im-
`munodeficiency virus (HIV) epidemic, new regula-
`tions were developed to accelerate approval for
`high-priority medications. Before then, drugs were
`approved based on their effect on the illness or on
`
`364 JABFP September–October 2001 Vol. 14 No. 5
`
`survival. Accelerated approval allowed the FDA to
`judge drugs using a surrogate endpoint, or the
`effect of the drug on a physiologic process or
`marker associated with a disease. For example,
`CD4 cell counts could be used to measure the
`effectiveness of an antiviral medication in treating
`HIV-infected patients. This new standard allowed
`the FDA to approve a promising drug without
`completing a full clinical trial.6
`
`Drug Development
`Drug development can generally be divided into
`phases. The first is the preclinical phase, which
`usually 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 an
`IND is approved, the next steps are clinical phases
`1, 2, and 3, which require approximately 1, 2, and 3
`years, respectively, for completion (Table 1). Im-
`portantly, throughout this process the FDA and
`investigators leading the trials communicate with
`each other so that such issues as safety are moni-
`tored. The manufacturer then files a new drug
`application (NDA) with the FDA for approval.
`This application can either be approved or rejected,
`or the FDA might request further study before
`making a decision. Following acceptance, the FDA
`can also request that the manufacturer conduct
`additional postmarketing studies. Overall, this en-
`tire process, on average, takes between 8 to 12
`years.2 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 preclinical
`testing, only one is approved for marketing.8 A
`1993 report by the Congressional Office of Tech-
`nology Assessment estimated the cost of developing
`a new drug to be $359 million.9 Newer figures
`place the cost at more than $500 million.10
`The first step, a preclinical phase, is to find a
`promising agent, which involves taking advantage
`of 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 to
`be a key component of a disease process, a re-
`searcher might seek ways to inhibit this enzyme.
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`Figure 1. Overview of drug development process and review. IND - investigational new drug, NDA - new drug
`application. Adapted from: The Drug Development Approval Process. Available at http://www.phrma.org/charts/
`approval.html.
`
`Advances in basic science might help by ascertain-
`ing the active enzyme site. Numerous compounds
`might be synthesized and tested before a promising
`agent emerges. Computer modeling often helps
`select what compounds might be the most promis-
`ing.
`The next step before attempting a clinical trial in
`humans is to test the drug in living animals, usually
`rodents. The FDA requires that certain animal tests
`be conducted before humans are exposed to a new
`molecular entity. The objectives of early in vivo
`testing are to demonstrate the safety of the pro-
`posed medication. For example, tests should prove
`that the compound does not cause chromosomal
`damage and is not toxic at the doses that would
`most likely be effective. The results of these tests
`are used to support the IND application that is filed
`with the FDA. The IND application includes
`chemical and manufacturing data, animal test re-
`sults, including pharmacology and safety data, the
`rationale for testing a new compound in humans,
`strategies for protection of human volunteers, and a
`plan for clinical testing.2,9 If the FDA is satisfied
`with the documentation, the stage is set for phase 1
`clinical trials.
`Phase 1 studies focus on the safety and pharma-
`cology of a compound.11 During this stage low
`
`doses of a compound are administered to a small
`group of healthy volunteers who are closely super-
`vised. In cases of severe or life-threatening ill-
`nesses, volunteers with the disease may be used.
`Generally, 20 to 100 volunteers are enrolled in a
`phase 1 trial. These studies usually start with very
`low doses, which are gradually increased. On aver-
`age, about two thirds of phase 1 compounds will be
`found safe enough to progress to phase 2.
`Phase 2 studies examine the effectiveness of a
`compound. To avoid unnecessarily exposing a hu-
`man volunteer to a potentially harmful substance,
`studies are based on an analysis of the fewest vol-
`unteers needed to provide sufficient statistical
`power to determine efficacy. Typically, phase 2
`studies involve 100 to 300 patients who suffer from
`the condition the new drug is intended to treat.
`During phase 2 studies, researchers seek to deter-
`mine the effective dose, the method of delivery (eg,
`oral or intravenous), and the dosing interval, as well
`as to reconfirm product safety.2,7,11,12 Patients in
`this stage are monitored carefully and assessed con-
`tinuously. A substantial number of these drug trials
`are discontinued during phase 2 studies. Some
`drugs turn out to be ineffective, while others have
`safety problems or intolerable side effects.
`
`The Drug Approval Process 365
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`Phase 3 trials are the final step before seeking
`FDA approval. During phase 3, researchers try to
`confirm previous findings in a larger population.
`These studies usually last from 2 to 10 years and
`involve thousands of patients across multiple sites.
`These studies are used to demonstrate further
`safety and effectiveness and to determine the best
`dosage. Despite the intense scrutiny a product re-
`ceives before undergoing expensive and extensive
`phase 3 testing, approximately 10% of medications
`fail in phase 3 trials.
`If a drug survives the clinical trials, an NDA is
`submitted to the FDA. An NDA contains all the
`preclinical and clinical information obtained during
`the testing phase. The application contains infor-
`mation on the chemical makeup and manufacturing
`process, pharmacology and toxicity of the com-
`pound, human pharmacokinetics, results of the
`clinical trials, and proposed labeling. An NDA can
`include experience with the medication from out-
`side the United States as well as external studies
`related to the drug.
`After receiving an NDA, the FDA completes an
`independent review and makes its recommenda-
`tions. The Prescription Drug User Fee Act of 1992
`(PDUFA) was designed to help shorten the review
`time. This act allowed the agency to collect user
`fees from pharmaceutical companies as financial
`support to enhance the review process. The 1992
`act specifies that the FDA reviews a standard drug
`application within 12 months and a priority appli-
`cation within 6 months. Application for drugs sim-
`ilar to those on the market are considered standard,
`whereas priority applications represent drugs offer-
`ing important advances in addition to existing
`treatments. If during the review the FDA staff feels
`there is a need for additional information or cor-
`rections, they will make a written request to the
`applicant. During the review process it is not un-
`usual for the FDA to interact with the applicant
`staff.12
`Once the review is complete, the NDA might be
`approved or rejected. If the drug is not approved,
`the applicant is given the reasons why and what
`information could be provided to make the appli-
`cation acceptable. Sometimes the FDA makes a
`tentative approval
`recommendation,
`requesting
`that a minor deficiency or labeling issue be cor-
`rected before final approval. Once a drug is ap-
`proved, it can be marketed.
`
`366 JABFP September–October 2001 Vol. 14 No. 5
`
`Some approvals contain conditions that must be
`met after initial marketing, such as conducting ad-
`ditional clinical studies. For example, the FDA
`might request a postmarketing, or phase 4, study to
`examine the risks and benefits of the new drug in a
`different population or to conduct special monitor-
`ing in a high-risk population. Alternatively, a phase
`4 study might be initiated by the sponsor to assess
`such issues as the longer term effects of drug expo-
`sure, to optimize the dose for marketing, to evalu-
`ate the effects in pediatric patients, or to examine
`the effectiveness of the drug for additional indica-
`tions.7 Postmarketing surveillance is important, be-
`cause even the most well-designed phase 3 studies
`might not uncover every problem that could be-
`come apparent once a product is widely used. Fur-
`thermore, the new product might be more widely
`used by groups that might not have been well
`studied in the clinical trials, such as elderly patients.
`A crucial element in this process is that physicians
`report any untoward complications. The FDA has
`set up a medical reporting program called Med-
`watch to track serious adverse events (1– 800-FDA-
`1088). The manufacturer must report adverse drug
`reactions at quarterly intervals for the first 3 years
`after approval,10 including a special report for any
`serious and unexpected adverse reactions.
`
`Recent Developments in Drug Approval
`The Food and Drug Administration Moderniza-
`tion Act of 1997 (FDAMA) extended the use of user
`fees and focused on streamlining the drug approval
`process.11,13 In 1999, the 35 drugs approved by the
`FDA were reviewed in an average of 12.6 months,
`slightly more than the 12-month goal set by
`PDUFA.10 This act also increased patient access to
`experimental drugs and facilitated an accelerated
`review of important new medications. The law
`ended the ban on disseminating information to
`providers about non–FDA-approved uses of medi-
`cations. A manufacturer can now provide peer-
`reviewed journal articles about an off-label indica-
`tion of a product if the company commits to filing
`a supplemental application to establish the use of
`the unapproved indication. As part of this process,
`the company must still conduct its own phase 4
`study. As a condition for an accelerated approval,
`the FDA can require the sponsor to carry out post-
`marketing studies to confirm a clinical benefit and
`product safety.
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`Critics contend the 1997 act compromises pub-
`lic safety by lowering the standard of approval.14
`Within a year after the law was passed, several
`drugs were removed from the market. Among these
`medications were mibefradil
`for hypertension,
`dexfenfluramine for morbid obesity, the antihista-
`mine terfenadine, and bromfenac sodium for
`pain.15 More recently, additional drugs including
`troglitazone were removed from the market. Al-
`though the increase in recalls might reflect the
`dramatic
`increase
`in
`drugs
`approved
`and
`launched,15 others argue that several safety ques-
`tions were ignored.16,17 Another concern was that
`many withdrawn drugs were me-too drugs which
`did not represent a noteworthy advance in therapy.
`Persons critical of the FDA believe changes in the
`approval process, such as allowing some new drugs
`to be approved based on only a single clinical trial,
`expanded use of accelerated approvals, and the use
`of surrogate end points, have created a dangerous
`situation.17 Proponents of the changes in the ap-
`proval process argue that there is no evidence of
`increased risk from the legislative changes,18 and
`that these changes improve access to cancer pa-
`tients and those with debilitating disease who were
`previously denied critical and lifesaving medica-
`tions.
`
`Conclusion
`New drugs are an important part of modern med-
`icine. Just a few decades ago, a disease such as
`peptic ulcers was a frequent indication for major
`surgery. The advent of new pharmacologic treat-
`ments has dramatically reduced the serious compli-
`cations of peptic ulcer disease. Likewise, thanks to
`many new antiviral medications, the outlook for
`HIV-infected patients has improved dramatically.
`It is important that physicians understand the pro-
`cess of approving these new medications. Under-
`standing the process can promote innovation, help
`physicians assess new products, underline the im-
`portance of reporting adverse drug events, and pro-
`vide physicians with the information to educate
`patients about participating in a clinical trial.
`
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`The Drug Approval Process 367
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