An overview of drug development in the United States and current challenges.

Abstract: Drug development in the United States has undergone many changes in the past 25 years, but relatively few fully realize the complexities involved in developing a new drug. Once a promising compound is identified, it must undergo preclinical testing, have an Investigational New Drug Application filed with the U.S. Food and Drug Administration (FDA), and proceed through clinical testing. When sufficient information is gained, a marketing application is filed with the FDA, who identifies it as a New Drug Application for drugs or a Biologics License Application for biologics. After FDA review and approval, postmarketing studies are frequently performed. The FDA and Congress have undertaken several initiatives to expand access and to accelerate drug development and review of investigational drugs for life-threatening and/or serious illnesses. Although the ultimate goal is to bring safer and more effective medical products to patients in a timely manner, multiple challenges face those who participate in drug development.

Key Words: investigational drugs, clinical trials, drug approval, Food and Drug Administration

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Drug development in the United States has undergone many changes in the past 25 years. Many entirely new classes of compounds are now available, and the scientific advances, including those in genomics and proteomics, indicate a promising future. Although it is well recognized that multiple stakeholders are affected by drug development, relatively few fully realize the complexities involved in developing a new drug and bringing it to market. This is especially important for physicians when using new medications (1) and when discussing medications with patients, who have increasing opportunities to gain health information through television, radio, newspapers, magazines, and the Internet.

In the current environment, many types of pressures--including scientific, socioeconomic, ethical, regulatory, and legal--continue to mount on both publicly and privately sponsored research. Each set of stakeholders has distinct expectations on necessary data whether they are academic and/or practicing physicians, formulary managers, patients and their families, government regulators from around the world, or scientists/managers from the companies developing the new products. This has led one pharmaceutical executive to conclude, "Satisfying the multiplicities of the demands for information that these varied 'customers' place on industry for information is a key force that drives today's large development programs." (2) This information usually involves such questions as these: Is the drug safe and does it work? What are the most appropriate endpoints for determining efficacy? How does it compare with currently available alternative therapies? Are there differences in population subgroups (eg, pediatrics, geriatrics, male/female patients, ethnic groups, renal insufficiency)? Is it cost-effective? Are there significant drug interactions? Does the drug prolong the QT interval? This article reviews general information regarding drug development processes, including the major regulatory requirements in the United States, and then assesses some of the current challenges in drug development.

U.S. Food and Drug Administration

Brief History

In the United States, the Food and Drug Administration (FDA) has broad oversight responsibilities for medical products. The main regulatory basis of the FDA's work originated with the Federal Food, Drug, and Cosmetic Act of 1938. Although earlier drug legislation existed, this Act established the authority of the FDA to require that new drugs demonstrate safety before they could be marketed. The Kefauver-Harris Drug Amendments, passed in 1962, then required new drugs to demonstrate efficacy before marketing. In the 1970s, the FDA's scope enlarged when the Public Health Service Bureau of Radiologic Health transferred to the FDA in 1971, the regulation of biologics transferred to the FDA from the National Institutes of Health (NIH) in 1972, and Medical Device Amendments were passed in 1976, establishing new regulatory procedures for medical device manufacturers. The Food and Drug Administration Act of 1988 officially established the FDA as an agency within the Department of Health and Human Services and noted that the President appoints the Commissioner of the FDA. This was followed by the Food and Drug Administration Modernization Act of 1997 (FDAMA), providing the most wide-ranging reforms in the FDA since 1938. The purposes of the FDAMA legislation included accelerated review of drugs and medical devices and regulation of advertising of unapproved uses of approved medical products. (3) Table 1 is a glossary of relevant abbreviations and acronyms.

Types of Medical Products Reviewed

There are three main types of medical products reviewed by the FDA as follows:

1. A drug includes "articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man ... and articles ... intended to affect the structure or any function of the body of man." (4)

2. A biologic is defined as "a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings." (5)

3. A medical device is "an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent ... which is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, or prevention of disease in man ... or intended to affect the structure or function of the body of man ... and which does not achieve its primary intended purposes through chemical action within or on the body of man ... and which is not dependent upon being metabolized for the achievement of its primary intended purposes." (6)

Sometimes, a fourth type of product is identified, a combination product. In this situation, a section of the FDA is designated to regulate the combination product, depending on the primary mode of action of the product. (7)

Organization

The FDA is organized into seven main centers (Fig. 1). Drugs are reviewed by the FDA's Center for Drug Evaluation and Research (CDER), and medical devices are reviewed by the Center for Devices and Radiological Health. Until recently, all biologics were reviewed by the Center for Biologics Evaluation and Review (CBER), but effective June 30, 2003, the FDA announced transfer of applications from the CBER to the CDER for most therapeutic biologics, including monoclonal antibodies for in vivo use, cytokines, growth factors, enzymes, immunomodulators, thrombolytics, proteins for therapeutic use (except clotting factors), and other non-vaccine therapeutic immunotherapies. Product classes to remain at the CBER included allergen patch tests; allergenics; antitoxins, antivenins, and venoms; in vitro diagnostics; vaccines; toxoids and toxins for immunization; blood, blood components, and related products; products composed of human or animal cells or from physical parts of those cells; and viral-vectored gene insertions. (8), (9)

Regulations versus Guidances

The FDA publishes many documents regarding requirements and instructions, two types of which include Regulations and Guidances. There are important differences between these types, as follows: Regulations are legally binding requirements found in Title 21 of the Code of Federal Regulations and must be followed, and Guidances represent the FDA's current thinking and recommendations but are not legally binding and do not supersede the Regulations. They usually contain greater detail about specified topics and can be updated more easily. Table 2 contains a listing of key FDA Regulations and Guidances in Good Clinical Practice.

Current Status of Drug Research and Development

At the end of 2002, the FDA reported that they had a total of 11,544 active Investigational New Drug Applications (IND). This included 4,158 commercial INDs and 7,386 noncommercial INDs. (10) Of the commercial INDs, five of the fastest-growing therapeutic areas by number of active INDs included central nervous system (with 466 active INDs), anti-inflammatory (413 active INDs), endocrine (378 active INDs), dermatologic (312 active INDs), and antivirals (206 active INDs). (11)

Research and development efforts in the United States are funded primarily by public/private corporations and the federal government. Between 1998 and 2003, the NIH budget grew an average of 15% per year, progressing from $13.7 billion to $27.2 billion. However, this growth rate may not be sustainable, as projections for 2003 to 2004 indicate only a 2.0% increase over current funding levels. (12)

In 2002, pharmaceutical companies spent an estimated $32 billion on research and development, which represented 18.2% of domestic sales. Over 80% of this total amount, $26.4 billion, was spent within the United States. (13)

Approximately 50,000 U.S. clinical investigators received funding for at least one clinical trial in 2002. Regarding the volume of clinical trial grants in the United States in 2002, CenterWatch estimates that $5.63 billion was spent, of which $3.23 billion (58%) was sponsored by major pharmaceutical companies, $1.10 billion by NIH, and $1.2 billion by other industry companies. The industry-sponsored clinical trial grants were divided primarily among part-time sites ($1.65 billion), academic medical centers/major medical centers ($1.57 billion), dedicated research sites ($1.00 billion), and site management organizations ($0.27 billion). (12)

Preclinical Research

After a promising compound is identified, much work occurs before human exposure, usually in vitro and with animal testing, requiring approximately 3 to 4 years. The goal is to limit the risk to patients as much as possible if the compound enters clinical trials. Usual types of studies that are performed include safety pharmacology studies (to assess drug effect on vital organ systems, such as the cardiovascular system, the respiratory system, and the central nervous system), single-dose acute toxicity studies, repeated-dose toxicity studies, local tolerance studies, at least part of the genotoxicity studies (bacterial reverse mutation test and chromosomal damage test), and possibly Carcinogenicity studies. Carcinogenicity studies are usually required for drugs used in chronic or recurrent conditions. Additional preclinical tests may be performed, sometimes concurrently with clinical trials, such as toxicokinetics and pharmacokinetics studies and reproduction toxicity studies. Specific requirements vary by country and with the specific drug and/or drug class. (14), (15)

Clinical Research Phases I to III

INDs

Once the decision is made from preclinical testing that use of the medical product appears promising and clinical testing should proceed, and before research studies begin with a new compound in human subjects, an IND must be filed by the sponsor with the FDA. The sponsor is defined by the FDA as "a person who takes responsibility for and initiates a clinical investigation." (16) Originally, a primary purpose of the IND was to provide an exemption from the illegality of shipping investigational drugs in interstate commerce without FDA approval. This application, as described in Title 21 of the Code of Federal Regulations (CFR), Part 312, now consists of multiple sections summarizing the general investigational plan, Investigator's Brochure (summarizing available safety and efficacy information in animals and humans, when available), protocol(s) for planned studies, chemistry/manufacturing/control information, and pharmacology/toxicology and other information. The FDA then has 30 days from receipt to review the application, and at the end of this period, the IND goes into effect and development work may proceed unless the FDA places a clinical hold on the investigation(s), as described in 21 CFR [section] 312.42. Additional information is then submitted periodically to the IND by the sponsor.

1. Protocol Amendments (21 CFR [section] 312.30). The new protocol for each clinical trial conducted under the U.S. IND must also be submitted to the FDA. The regulations specify that the protocol may be submitted before or after Institutional Review Board (IRB) approval, but both actions are required before subjects are enrolled. If the FDA has concerns with the study at any point during its conduct, they may institute a clinical hold, halting from one study to the complete clinical trial program, until further information is supplied and/or additional requirements are met. Changes to the protocol that affect the safety of subjects must also be submitted to the FDA. In addition, for Phase II or III protocols, changes that significantly affect the scope of the investigation or the scientific quality of the study must be submitted. With each protocol conducted under the IND, the sponsor must also submit information on all of the investigators participating in the study to the FDA. The sponsor submits the investigators' information contained on the Form FDA 1572, which includes obligations by which the investigators agree to abide during the study, and the curriculum vitae of the principal investigator. Any revisions made to the Form FDA 1572s during the study are also submitted to the FDA, originating from any change in investigators/subinvestigators, location of the research, laboratory facilities, IRB, and protocol name or number. Additional information may be submitted, depending on specific federal requirements and/or practices of the sponsor, such as informed consent form information.

2. Information Amendments (21 CFR [section] 312.31). This is the second type of amendment to an IND, and is used to report essential information not included in other amendments or reports. Examples of such information might include new toxicology, chemistry, other technical information, or a report concerning the discontinuation of a clinical investigation.

3. IND Safety Reports (21 CFR [section] 312.32). All reports of serious, unexpected adverse events associated with use of the study drug must be reported to the FDA and all participating investigators in a written report within 15 calendar days after the sponsor received the initial information. The written report may be in narrative format, on a MedWatch form (Form FDA 3500A, from manufacturers), or on a Council for International Organizations of Medical Sciences I form (usually reserved for foreign events, depending on the sponsor's procedures). If the adverse event involved an unexpected fatal or life-threatening event associated with use of the drug, the FDA must also be notified by telephone or facsimile transmission within 7 calendar days of the sponsor's initial notification. When relevant follow-up information is received on all IND Safety Reports, a follow-up written report must again be submitted within the same time frames. It is important to note that not all serious adverse events occurring in clinical trials result in IND Safety Reports. Although the investigators commonly report all serious adverse events to the sponsor with their causality assessment, expected events do not meet expedited reporting criteria in the United States. However, multinational sponsors also need to comply with foreign reporting requirements, which may be different. In addition, the term "serious," as defined in FDA regulations, should not be confused with the term "severe," a clinical term. Serious adverse events are not always severe.

4. Annual Reports (21 CFR [section] 312.33). Each year after the IND became effective, the sponsor must submit a progress report of the development work. Summary information is required on each individual study in progress and completed during the year in addition to overall information from the preclinical/clinical work, including the most frequent and most serious adverse experiences, IND Safety Reports, subject deaths and subject dropouts during the trial(s), dose response findings, preclinical findings, any significant manufacturing changes, the general investigational plan, whether the Investigator Brochure has been revised, foreign marketing developments, and other items.

Investigators' Obligations

Investigators perform critical functions in the clinical research process, enrolling subjects, collecting the data, and providing training and oversight to site personnel. FDA regulations address the responsibilities of investigators in 21 CFR [section][section] 312.60 to 312.69, and the scope includes the following actions:

* Conduct the investigation according to the signed Form FDA 1572 (which also lists investigator commitments on the second page), the protocol, and applicable regulations.

* Protect the rights and welfare of subjects participating in the trial, obtaining informed consent according to the provisions of 21 CFR Part 50.

* Administer the investigational drug only to authorized subjects and under the personal supervision of the investigator or subinvestigator.

* Maintain adequate records of the study drug disposition.

* Prepare and maintain "adequate and accurate case histories" of all subjects participating in the trial.

* Retain study records for the required length of time.

* Provide progress reports to the sponsor and promptly report adverse effects.

* Provide financial disclosure reports to the sponsor, in accordance with 21 CFR Part 54.

* Ensure that an IRB in compliance with 21 CFR Part 56 is responsible for initial and continuing review approval of the study and that all changes in the research activity and unanticipated problems are reported promptly.

* Allow FDA officers access to inspect study records on request.

Institutional Review Board

Another critical participant in the research process is the IRB. Since 1971, clinical research studies have been reviewed by the IRB and the FDA. The purpose of the IRB's review is to ensure that the rights and welfare of all study participants are protected, risks are minimized and reasonable in relation to potential benefits, selection of subjects is equitable, proper informed consent is obtained from each participant, the study is scientifically valid, and subjects' privacy and the confidentiality of the data are maintained. (17)

This latter provision has prompted most IRBs to review (and often grant approval) to Health Insurance Portability and Accountability Act (HIPAA) authorizations, in use since April 14, 2003. HIPAA authorizations are now obtained at "covered entities" from any newly enrolled study participants to allow sponsors, their representatives, or the FDA to access medical records and/or collect data containing subjects' protected health information. HIPAA authorizations may either be incorporated into the Informed Consent form or prepared as a separate document. Although IRBs always review the Informed Consent form for approval, some IRBs use a different process when the HIPAA authorization is a separate form.

In all cases, however, the protocol and Informed Consent form must be approved by the IRB before any subject participation, and changes cannot be made in the research without IRB approval, except as stated in 21 CFR [section] 312.66, "where necessary to eliminate apparent immediate hazards to human subjects." IRBs also specify the types and frequency of reporting required of investigators during ongoing clinical trials.

As listed in Table 2, two specific parts of the FDA regulations govern IRB structure and function: 21 CFR Part 56 concerns the IRB itself and 21 CFR Part 50 concerns requirements of informed consent. The FDA has also issued Information Sheets, listed in Table 3, which provide helpful guidance to IRBs and clinical investigators. If the IRB reviews federally supported human subject research, the IRB must file an "Assurance" of protection for human subjects with the Office of Human Research Protection (OHRP). After December 31, 2003, all IRBs with an Assurance must have the new Federalwide Assurance of Protection for Human Subjects from the OHRP. In addition, IRBs with the Federalwide Assurance are required to register with the OHRP, but IRB registration is not currently required by the FDA. The OHRP Web site contains an online IRB guidebook, which also contains helpful information for IRBs.

Contract Research Organizations

When sponsors need additional resources and/or therapeutic expertise to conduct their clinical trials, they may use one or more contract research organizations (CRO). A CRO is defined in 21 CFR [section] 312.3(b) as "a person that assumes, as an independent contractor with the sponsor, one or more of the obligations of a sponsor." When sponsor obligations are transferred to a CRO, the FDA must be informed of the "Transfer of Obligations." Types of duties that may be outsourced include site monitoring, project management, shipping of clinical trial supplies, data management, statistical analysis, and other duties. The CRO is then held to the same standards as the sponsor for the transferred duties.

Phase I Studies

The clinical development work generally proceeds in three separate phases (Fig. 2), but in selected situations, the development framework may be compressed. Phase I studies usually involve between 20 and 80 healthy adult volunteers and require an average of 12 to 18 months to complete. The purpose of these studies is to determine drug safety and side effects with increasing dosage. Pharmacokinetic and pharmacologic actions of the drug (absorption, distribution, metabolism, and elimination information) are studied to assist with the design of scientifically valid Phase II studies. (18)

Phase II Studies

Phase II studies usually involve between 100 and 300 patients with the disease or condition under study and often require at least 2 years to complete. The purpose of these studies is to determine whether the medical product is effective and to collect additional short-term safety information. The studies are generally randomized and double-blind, and have a control group and one or more treatment groups.

Phase III Studies

Phase III studies usually involve several hundred to several thousand patients, depending on the product and disease being studied, and require 3 or more years. Trials may include both controlled and uncontrolled (open-label) trials. Eligibility criteria are typically not quite as strict as in Phase II because more is known about the product at this stage, and data on drug safety and efficacy are collected from a more diverse population. (18), (19)

New Drug Applications

When the sponsor has collected sufficient information from preclinical and clinical studies to provide the FDA with data for analysis of the safety and efficacy of the study drug, they submit an application for marketing. These applications have different content and names, depending on the type of compound, as follows:

* For new drugs: the New Drug Application (NDA).

* For biologics: the Biologics License Application (BLA); formerly, two separate applications were required, the Product License Application and the Establishment License Application.

* For medical devices: Premarket Approval Application. However, some devices may be marketed with a Premarket Notification 510(k), and some devices are exempt.

* For generic drugs: the Abbreviated New Drug Application.

* The new harmonized format approved for use in International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) regions: the Common Technical Document. The ICH is a joint initiative among regulatory agencies and industry to develop common standards on the safety, quality, and efficacy of medical products. The ICH's work began in 1990 between the United States, the European Union, and Japan to seek harmonization of registration requirements for drugs and biologics. As of July 2003, the Common Technical Document format for new drug submissions is required in Japan and the European Union and "highly recommended" in the United States. Although the format is the same in these three regions, the actual content may differ.

[FIGURE 2 OMITTED]

Extensive information is submitted for NDAs and includes such topics as proposed labeling, chemistry/manufacturing/controls, nonclinical pharmacology and toxicology, human pharmacokinetics and bioavailability, microbiology (for anti-infectives), clinical data (with extensive results of clinical trials on safety and efficacy to support the claimed indications), an integrated safety summary, an integrated summary of the benefits and risks of the drug, statistical analyses, pediatric information, case report forms and tabulations, patent information, and financial disclosure information.

The FDA Review Process

Once the FDA receives an application for marketing approval, a team performs the medical, biopharmaceutical, statistical, and microbiology (for anti-infective drugs) reviews to study and validate the sponsor's conclusions. The review process takes a variable length of time, depending on the specific medical product, but has required months to years for most new drugs and biologics. The FDA is frequently in communication with the sponsor and may request additional information. The FDA may perform inspections, particularly of selected investigator sites in pivotal clinical trials to verify the data and of sponsor manufacturing facilities. On occasion, the FDA may inspect sponsors and/or CROs. If the inspections involve the clinical studies, FDA staff use the Compliance Program Guidance Manual section 7348.811 for sponsors, CROs, and monitors and section 7348.811 for Clinical Investigators. When the review process is nearing completion, the results may be reviewed by the pertinent FDA Advisory Committee, which will decide whether to recommend the product for FDA approval. The FDA carefully considers the input from these expert advisors, but their recommendations are not binding. Other major decisions before product approval include negotiation of package labeling with the sponsor and the decision regarding whether postmarketing work will be required.

Postmarketing Studies

Once a medical product receives marketing approval, there are several reasons why additional clinical studies may be needed, such as Phase IV commitments required of or agreed to by the sponsor, pharmacoeconomic studies to assess cost/benefit, investigator-initiated studies, and quality-of-life studies. (Studies conducted to obtain information for potential new indications are actually Phase III studies, even though the product is marketed, and the data are submitted to the FDA in a supplemental NDA.)

Numerous Phase IV commitments have been required by the FDA, such as those associated with accelerated approval (discussed below). Since 1997, when the FDAMA was enacted, [section] 130(a) of Title I of this Act has required sponsors to annually inform the FDA of their progress in completing those studies addressing safety and efficacy. Between 1991 and 2000, the FDA approved 1,090 NDAs (drugs) that, with supplemental applications, required 1,737 commitments under FDAMA [section] 130 implementation. During this same period, the FDA approved 163 BLAs (biologics) that, with supplemental applications, generated 193 commitments under FDAMA [section] 130 implementation. (20)

Pathways for Expanded Access and Accelerated Approval

Recognizing that drug development and approval is a complex process, the FDA and Congress established mechanisms by which access to drugs for life-threatening and/or serious illnesses could be facilitated.

Expanded Access: Orphan Drugs 

In January 1983, the Orphan Drug Act (21) was passed to encourage development of treatments for rare diseases and conditions. The original definition of a rare disease was refined with an amendment in October 1984 to specify that the condition affected less than 200,000 patients in the United States or affected more than 200,000 patients in the United States but "there was no reasonable expectation that the cost of developing and making available ... a drug ... will be recovered from sales in the US ...." (22) Assistance included tax incentives, help with study design from the FDA, possible Phase I/II grant funding, and 7 years of marketing exclusivity after FDA approval. As of August 2003, more than 1,000 products had been designated as orphan products. A total of 231 orphan drugs have been approved, including clofazimine for lepromatous leprosy, coagulation factor IX for hemophilia, ifosfamide for testicular cancer, and imatinib for chronic myelogenous leukemia. (23)

Treatment IND 

In 1987, Treatment INDs were introduced (24) (and later codified in 21 CFR [section] 312.34) to allow expanded access to promising drugs for patients who did not meet criteria to enter clinical trials, usually already in Phase III, in two types of situations: 1) in serious or life-threatening disease with drugs having preliminary evidence of efficacy, and 2) in diseases with no comparable treatment for the specific disease stage. (These regulations actually built on procedures established with the Group C program, started in 1976 between the FDA and the National Cancer Institute, to provide expanded access to cancer drugs.) The sponsor had to actively seek marketing approval, and IRB approval and Informed Consent were still required before enrolling subjects (unless a waiver was granted). Treatment INDs were also used to allow expanded access while the FDA was reviewing the marketing application. (25) In this situation and with prior FDA approval, patients could be charged for the therapy to compensate the sponsor for costs associated with expanded drug access before commercial distribution. In the decade that followed, treatment IND protocols were used for 11 promising acquired immunodeficiency syndrome (AIDS)-related drugs, (26) 13 oncology drugs, and 14 drugs for other indications.

Parallel Track

When AIDS began affecting larger numbers of patients, and approved medications were very limited, the U.S. Public Health Service established this additional mechanism in 1992 (27) to allow patients access to investigational medications when they could not take standard medications and did not meet criteria to participate in clinical trials. Later that year, stavudine (d4T) (Zerit; Bristol-Myers Squibb, New York, NY) was the first drug submitted for consideration. Before FDA approval, over 12,000 patients received d4T by the parallel track mechanism. However, no other drugs have been submitted for consideration under this mechanism. (26)

Emergency Use IND

Emergency use of an investigational drug is described in 21 CFR [section] 312.36 and includes instructions to follow when access is needed to an investigational agent before an IND can be submitted. The FDA can authorize shipment of the investigational agent, but the FDA requires the sponsor to submit the IND "as soon as practicable after receiving the authorization."

Special Protocol Exception

This type of access has been frequently referred to as "compassionate use," although the term never appears in FDA regulations, (28) because the patient receives the investigational medication outside of clinical trials. It is used in certain situations when a patient does not qualify for ongoing clinical trials but may benefit from the investigational agent. The request is initiated by a sponsor, usually on the recommendation of an investigator, and requires consultation with the FDA, usually modification of the Informed Consent form, and IRB approval. (29)

Accelerated Approval: Subpart E Procedures

This name for this first method of accelerated development/review came from the Subpart E section of 21 CFR Part 312 (ie, 21 CFR [section][section] 312.80-312.88). (30) These regulations built on the process used for the first AIDS drug, azidothymidine (zidovudine), and were applicable to drugs/biologics for life-threatening or severely debilitating diseases. These procedures included increased communication with the FDA, active monitoring and evaluation of clinical trials by the FDA, consideration of treatment Investigational New Drug designation at the end of Phase II, elimination of Phase III clinical trials, and the potential request to conduct Phase IV trials. By the end of 1994, 28 drugs had received Subpart E approval, including 10 for AIDS- and human immunodeficiency virus-related conditions and seven for cancer. (25)

Accelerated Development/Review

In December 1992, a new process was introduced to expedite development and FDA review of promising medications for serious or life-threatening diseases without existing treatment. (31) It was later incorporated into FDAMA [section] 112 (21 USC [section] 356). This mechanism applied when FDA approval was 1) based on beneficial treatment effect on a "surrogate endpoint," which was not necessarily a physical sign or laboratory finding indicating functional status or survival but still helped predict therapeutic benefit; and 2) associated with restricted distribution or use. (An example of a surrogate endpoint used with early AIDS drugs was the CD[4.sup.+] lymphocyte count.) After the accelerated market introduction, the FDA could require the sponsor to continue postmarketing studies to confirm therapeutic benefit. If clinical benefit was not observed or if the sponsor did not complete the required studies, the FDA could withdraw the product.

Fast Track

"Fast track" was a mechanism introduced in the FDAMA intended to apply to a specific drug for a specific indication. To qualify for fast track designation, there were two requirements: 1) the product must be used in a serious or life-threatening condition; and 2) the product must have the potential to address an unmet medical need, and the studies would evaluate this potential. The sponsor could apply for fast track designation at any time after the IND submission and before the NDA or BLA submission. Advantages of this designation included frequent meetings with the FDA (pre-IND consultation, end of Phase I meeting, end of Phase II meeting, pre-BLA/NDA meeting, and meeting to discuss labeling issues), written correspondence from the FDA addressing design of pivotal trials and Phase II/III development plans, and that portions of an application could be submitted for review before the complete application. (32) Products in fast track development programs could also qualify for priority review and accelerated approval (as described in other sections).

Priority Review

According to the FDAMA legislation, once an application was submitted to the FDA for marketing approval, it was designated as Standard Review or Priority Review. Standard Reviews had a target date to complete review of the application and to determine whether or not to grant approval at 10 months after the filing date. Priority Reviews had a 6-month target date for this process. To qualify for Priority Review, a product must address an unmet medical need, which was defined by the CBER as "a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious or life-threatening disease." However, the CDER also allowed Priority Reviews for nonserious diseases. (33), (34)

Current Challenges in Drug Development

With the increasing pressures to bring safer and more effective drugs to patients faster, to realize the potential of the genomic information explosion, and to make these new therapies affordable, complex challenges have faced those who participate in drug development. A brief summary of some of the current challenges affecting research participants is presented below.

Investigators

Two specific areas affecting investigative sites have recently received much attention. The first consists of increased training and documentation required to conduct studies. Areas in which training and documentation are now needed, in addition to study protocol procedures, include the following:

* Good Clinical Practice (Rutan et al (35) were among those who studied the need for additional training).

* Protection of patient privacy and the HIPAA regulations.

* Shipping of hazardous materials (eg, blood and body fluids, certain study medications); training requirements in 49 CFR [section] 172.702 have been cited by the Federal Aviation Administration on previous site inspections because these materials are usually sent by overnight air carrier. (36)

* Security and validation of electronic medical records, if used. The FDA regulations 21 CFR Part 11 concern electronic records and electronic signatures.

The second area consists of adequate oversight of the research by the principal investigator. The FDA expects that the principal investigator will "personally conduct or supervise the investigation," and they have previously issued warning letters to investigators citing this finding. (37)

Institutional Review Boards

According to the Mark Yessian, Regional Inspector General for Evaluation and Inspections, (38) IRBs "face major changes in the research environment" as studies become larger and more complex. Resources may be strained, as they are expected to review large volumes of work within a relatively short period of time, and training is very important. Organizations such as the American Society of Clinical Oncology have noted that "an effective oversight process ... can only be accomplished by the involvement of an experienced IRB that receives funding, resources, and institutional support enabling it to fulfill its mandate." (39) To document their quality commitment, some IRBs are now seeking accreditation, currently available from the Association for the Accreditation of Human Research Protection Programs or the National Committee for Quality Assurance, now teamed with the Joint Commission on Accreditation of Healthcare Organizations in the Partnership for Human Research Protection.

Sponsors

The most common risks mentioned by sponsors with drug development involve time and costs. When the public considers drug development, many express concerns about the price of prescription drugs. Drug prices are affected by the long and complex research and development processes together with the low rate of identified compounds that actually make it to drug approval (Fig. 2). To obtain sufficient information from discovery through marketing approval requires an average time frame of 10 to 15 years. (40) Although the patent is granted for 20 years, the development and regulatory approval time is included in this period.

To remain financially viable, the company must be able to recoup a significant portion of its investment within the remaining patent life after regulatory approval. Tufts University Center for the Study of Drug Development now estimates the development cost for a single new drug at $897 million. (41) To obtain this figure, DiMasi et al (42) estimated average out-of-pocket cost per new drug at $403 million, and then added in capitalized out-of-pocket costs, using a real discount rate of 11%, to obtain a total cost to marketing approval of $802 million. The remaining $95 million represents postapproval research and development costs. However, additional work from this group revealed that 70% of drugs studied never generate sufficient revenue to recoup the mean cost of development. (43) Economic pressures may continue to increase with pharmaceutical manufacturers if current provisions in the Medicare legislation are enacted concerning drug reimportation and patent challenges by generic drug manufacturers.

FDA

The FDA continually experiences pressures from approving new drugs either too slowly or too quickly. Figure 3 indicates the number of new drugs approved annually by the FDA from 1988 to 2002. The Prescription Drug User Fee Act and FDAMA provisions have had positive effects on accelerated development and expanded access, but several drugs were withdrawn from the market after the new laws (eg, mibefradil, dexfenfluramine, terfenadine, bromfenac, and troglitazone) and debate ensued. (44-47) However, further analysis did not reveal evidence of increased risk from regulatory actions. (48) To further drug safety efforts, the FDA has undertaken new risk management initiatives to increase postmarketing surveillance and reduce medication errors. (49)

Conclusion

The research and development processes involved in bringing a new drug to market are complex. Efforts of the sponsor, investigators, IRBs, subjects participating in clinical trials, and the FDA are all essential. On average, only 1 compound from the original 5,000 to 10,000 screened complete the process to FDA approval, after which postmarketing studies and safety surveillance efforts continue. The goal remains to bring safer and more efficacious medications to patients to improve their health and quality of life.

[FIGURE 3 OMITTED]

They are as sick, That surfeit too much, As they that starve with nothing.

--William Shakespeare, Merchant of Venice

Table 1. Glossary of abbreviations and acronyms

Abbreviation or
acronym                              Term

ANDA             Abbreviated New Drug Application

BLA              Biologic License Application

CBER             Center for Biologics Evaluation and Review

CDER             Center for Drug Evaluation and Review

CDRH             Center for Devices and Radiologic Health

CFR              Code of Federal Regulation

CRO              Contract Research Organization

CTD              Common Technical Document

ELA              Establishment License Application

EMEA             European Agency for the Evaluation of Medicinal
                   Products

FDA              Food and Drug Administration

FDAMA            Food and Drug Administration Modernization
                   Act of 1997

GCP              Good Clinical Practice

HIPAA            Health Insurance Portability and Accountability
                   Act of 1996

ICH              International Conference on Harmonization of
                   Technical Requirements for Registration of
                   Pharmaceuticals for Human Use

IDE              Investigational Device Exemption

IEC              Independent Ethics Committee

IND              Investigational New Drug

IRB              Institutional Review Board

MHLW             Ministry of Health, Labor, and Welfare

NDA              New Drug Application

OGCP             Office of Good Clinical Practice

OHRP             Office for Human Research Protections

ORA              Office of Regulatory Affairs

PDUFA            Prescription Drug User Fee Act

PLA              Product License Application

PMA              Premarket Approval of Medical Devices

SMO              Site Management Organization

SNDA             Supplemental New Drug Application

TPP              Therapeutic Product Programme

Abbreviation or
acronym                            Brief description

ANDA             Usual application from a sponsor to the FDA for
                 marketing approval of a generic drug

BLA              Current type of application (since 1997) from a sponsor
                 to the FDA for marketing
                   approval of a biologic

CBER             Center of the FDA with oversight of vaccines, blood
                 products, antitoxins, allergenics,
                   and "gene therapy"

CDER             Center of the FDA with oversight of drugs and most
                 biologic therapeutic products

CDRH             Center of the FDA with oversight of medical devices,
                 radiation-emitting electronic
                   products (medical and nonmedical)

CFR              Listing of U.S. federal regulations

CRO              An independent contractor who assumes one or more
                 obligations from a sponsor

CTD              The type of core licensing application from a sponsor
                 to regulatory authorities in ICH
                   regions for marketing approval of medical products;
                 required (and replacing previous
                   types of new product applications) as of July 1, 2003
                 in Europe, Japan, Canada, and
                   "highly recommended" in the United States to the FDA

ELA              Before 1997, the type of application the FDA required
                 from a company for licensing
                   the establishment to produce a biologic product

EMEA             Drug regulatory agency of Europe

FDA              Federal agency in the United States that oversees
                 safety/efficacy of drugs, biologics,
                   devices, foods, food additives, dietary supplements,
                 and cosmetics

FDAMA            New regulations that streamlined clinical testing
                 requirements and allowed greater
                   access to investigational drugs for
                 serious/life-threatening diseases; stimulated studies
                   in pediatric patients by granting additional
                 marketing exclusivity for obtaining these
                   data

GCP              Standards for the entire scope of activities within
                 clinical trials to ensure the rights of
                   subjects are protected and that the data are accurate

HIPAA            Complex law passed in 1997, one provision of which
                 discusses use and disclosure of
                   patients' protected health information

ICH              A joint initiative among regulatory agencies and
                 industry in the United States, the
                   European Union, and Japan to develop common standards
                 on the safety, quality, and
                   efficacy of medical products

IDE              Type of application from a sponsor for use of an
                 investigational medical device in
                   clinical trials

IEC              A group similar to an IRB, charged with oversight of
                 human subject protection in
                   clinical trials, usually outside the United States

IND              Type of application from a sponsor for use of an
                 investigational drug or biologic in
                   clinical trials

IRB              An independent body whose primary role is the
                 protection of the rights, safety, and
                   well-being of clinical trial participants

MHLW             Drug regulatory agency of Japan

NDA              Usual application from a sponsor to the FDA for
                 marketing approval of a drug

OGCP             Office to coordinate GCP efforts within the FDA and
                 with other federal agencies

OHRP             Federal office charged with oversight of human subject
                 protection in research for the
                   Department of Health and Human Services (regulations
                 45 CFR Part 46)

ORA              Center of the FDA with oversight of field activities of
                 FDA and enforcement

PDUFA            Law first passed in 1992, subsequently reauthorized in
                 1997 (PDUFA II) and 2002
                   (PDUFA III); authorizes the FDA to collect fees from
                 sponsors for review of
                   products' marketing applications, allowing the FDA to
                 hire more reviewers and
                   complete the work faster

PLA              Before 1997, the type of application the FDA required
                 from a sponsor for marketing
                   approval of a biologic product

PMA              Type of application from a sponsor to the FDA for
                 marketing approval of a medical
                   device

SMO              An independent contractor who assumes one or more
                 regulatory obligations from an
                   investigator

SNDA             A marketing application from a sponsor to the FDA
                 requesting changes in a drug's
                   approved NDA (eg, a new indication)

TPP              Drug regulatory agency of Canada

Fig. 1 Diagram depicting FDA centers.

                        FDA Center                   Oversight Includes:

CDER   Center for Drug Evaluation and Research       Drugs, most
                                                     biologic
                                                     therapeutic
                                                     products

CBER   Center for Biologics Evaluation and Research  Vaccines, blood
                                                     products,
                                                     antitoxins,
                                                     allergenics, "gene
                                                     therapy"

CDRH   Center for Devices and Radiological Health    Medical devices,
                                                     radiation-emiting
                                                     electronic products
                                                     (medical
                                                     and nonmedical)

CVM    Center for Veterinary Medicine                Animal drugs and
                                                     food additives

NCTR   National Center for Toxicological Research    Research to support
                                                     FDA's current and
                                                     future regulatory
                                                     needs

CFSAN  Center for Food Safety and Applied Nutrition  Foods, food
                                                     additives, food
                                                     labels, dietary
                                                     supplements,
                                                     cosmetics

ORA    Office of Regulatory Affairs                  Field activities of
                                                     FDA, enforcement

Table 2. Key Food and Drug Administration
Regulations/Guidances in Good Clinical Practice (a)

Reference                                Regulation

21 CFR Part 11        Electronic Records; Electronic Signatures
  FDA Draft Guidance  Part 11, Electronic Records, Electronic
                        Signatures--Scope and Application (issued
                        February 2003)

21 CFR Part 50        Protection of Human Subjects

21 CFR Part 54        Financial Disclosure by Clinical Investigators
  FDA Guidance        Financial Disclosure by Clinical Investigators
                        (issued March 20, 2001)

21 CFR Part 56        Institutional Review Boards

21 CFR Part 312       Investigational New Drug Application

21 CFR Part 314       Applications for FDA Approval to Market a
                        New Drug

21 CFR Part 600       Biologic Products; General

21 CFR Part 812       Investigational Device Exemptions

21 CFR Part 814       Premarket Approval of Medical Devices
  ICH E6 Guidance     Good Clinical Practice: Consolidated Guidance
                        (issued by the FDA in April 1996)

(a) CFR, Code of Federal Regulations; FDA, Food and Drug Administration;
ICH, International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use.

Table 3. Selected federal Web sites with helpful information for
investigators and clinicians (as of August 11, 2003) (a)

Site                                         Brief Description

Regulations/Notices/Guidances

  Code of Federal Regulations, Title  FDA regulations
  21 (21 CFR)

  Federal Register                    Complete version of this daily
                                      publication, which contains
                                        federal government rules,
                                      proposed rules, notices, and
                                        presidential documents

                                      Federal Register home page for
                                      FDA-related material

  FDA-Issued Guidances                Home page for FDA Guidance
                                      Documents
                                      Topical listing with links to
                                      Guidances from the Centers
                                        for Drugs and Biologics
                                      ICH Guidance on Good Clinical
                                      Practice

Additional resources

  Consumer Drug Information           Information written for consumers
                                      on newer prescription
                                         drug products (approved by the
                                      FDA since 1998)

  Drug Shortages                      Listings of drugs with current or
                                      resolved shortages, and
                                        drugs to be discontinued or
                                      recalled

  FDA Information Sheets              FDA guidance (for IRBs and
                                      Clinical Investigators) on
                                        protection of human subjects
                                      participating in research

  FDA MedWatch Program                Safety information from the FDA on
                                      U.S. medical
                                        products and reporting of
                                      adverse reactions

  Office of Good Clinical Practice    Home page of the office that
                                      serves as a central point for
                                       issues involving clinical
                                      research regulated by the FDA

  Office for Human Research           The office within the Department
                                      of Health and Human
  Protections                           Services that oversees IRBs
                                      reviewing federally funded
                                      research

                                      IRB Guidebook (Office for Human
                                      Research Protection's
                                        guidance for IRBs)

  Office of Regulatory Affairs:       Introductory page of various
                                      compliance documents,
  Compliance References                  including listing of
                                      investigators restricted from
                                         receiving investigational
                                      products

                                      Compliance Program Guidance Manual
                                      sections, such as
                                        for IRBs and Clinical
                                      Investigators

  "Orange Book"                       Searchable listing of FDA-approved
                                      prescription and
                                        over-the-counter drug products

Site                                                URL

Regulations/Notices/Guidances

  Code of Federal Regulations, Title  http://www.access.gpo.gov/cgi-bin
  21 (21 CFR)                         /cfrassemble.cgi?title=200221

  Federal Register                    http://www.gpoaccess.gov/fr/index.
                                      html

                                      http://www.accessdata.fda.gov/
                                      scripts/oc/ohrms/index.cfm

  FDA-Issued Guidances                http://www.fda.gov/opacom/
                                      morechoices/industry/guidedc.htm

                                      http://www.fda.gov/cder/guidance/
                                      guidance.htm

                                      http://www.fda.gov/cder/guidance/
                                      959fnl.pdf

Additional resources

  Consumer Drug Information           http://www.fda.gov/cder/
                                      consumerinfo/default.htm

  Drug Shortages                      http://www.fda.gov/cder/drug/
                                      shortages/default.htm

  FDA Information Sheets              http://www.fda.gov/oc/ohrt/irbs/
                                      default.htm

  FDA MedWatch Program                http://www.fda.gov/medwatch/index.
                                      html

  Office of Good Clinical Practice    http://www.fda.gov/oc/gcp/

  Office for Human Research           http://ohrp.osophs.dhhs.gov/
  Protections
                                      http://ohrp.osophs.dhhs.gov/irb/
                                      irb_guidebook.htm

  Office of Regulatory Affairs:       http://www.fda.gov/ora/compliance_
  Compliance References               ref/

                                      http://www.fda.gov/ora/compliance_
                                      ref/bimo/default.htm

  "Orange Book"                       http://www.fda.gov/cder/ob/
                                      default.htm

(a) CFR, Code of Federal Regulations; FDA, Food and Drug Administration;
ICH, International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use; IRB,
Institutional Review Board.

Accepted September 29, 2003.

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(4.) 21 U.S. Code [section] 321(g).

(5.) 42 U.S. Code [section] 262(i).

(6.) 21 U.S. Code [section] 321(h).

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RELATED ARTICLE: Key Points

* Of the 5,000 to 10,000 compounds screened, an average of 1 will proceed through development to Food and Drug Administration approval.

* Developing a new drug requires approximately 10 to 15 years and is estimated to cost $897 million.

* Drug development requires the joint efforts of the sponsor, investigators, Institutional Review Boards, subjects participating in clinical trials, and the Food and Drug Administration.

Sharon Wyatt Moore, MD, MBA, MPH

From Medical and Regulatory Affairs, Clinical Trial Management Services, Inc., Bristol, TN; James H. Quillen Veterans Affairs Medical Center, Mountain Home, TN; and the Department of Geriatrics, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

Reprint requests to Sharon Wyatt Moore, MD, MBA, MPH, Medical and Regulatory Affairs, Clinical Trial Management Services, Inc., 1241 Volunteer Parkway, Suite 950, Bristol, TN 37620. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9612-1244