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The process of clinical development and regulatoryreview of new therapeutics in the United States hasundergone significant change since 1980. The primaryconcerns that prompted the alterations were a lack ofaccess to innovative therapeutics and the lengthyapproval process1. Addressing these concerns was notsimply a matter of reducing the time between discoveryand approval, but rather of inspiring the developmentof products that were superior to existing treatmentsand which could satisfy unmet medical needs, especiallyfor serious or life-threatening diseases. Three legislativeacts implemented in the 1980s worked in concert tostimulate the discovery and development of therapeu-tics: the Patent and Trademark Amendments of 1980(also known as the Bayh–Dole Act), the Orphan DrugAct of 1983, and the Drug Price Competition andPatent Term Restoration Act of 1984 (also known asthe Hatch–Waxman Act).

The Bayh–Dole Act allowed federal agencies suchas the National Institutes of Health (NIH), as well as

NIH grantees and contractors, to patent discoveriesand license these patents to commercial entities. TheAct thereby facilitated the transfer of technology fromthe government and universities, where the focustends to be on basic research, to industry, where com-mercialization of products is the goal2. The OrphanDrug Act was designed to facilitate the development oftreatments for rare diseases or conditions (those witha prevalence of less than 200,000 patients in the UnitedStates, or those that affect more than 200,000 people,but for which there is no reasonable expectation thatthe costs for development would be recovered fromUS sales). Companies that develop orphan drugs areprovided with various incentives, including sevenyears of marketing exclusivity (starting on the product’sapproval date), a 50% tax credit for money spent onclinical studies for the orphan indication, protocolassistance and clinical research grants from the FDA,an exemption from application user fees, and a waiverof product and establishment fees3.

TRENDS IN DEVELOPMENT ANDAPPROVAL TIMES FOR NEW THERA-PEUTICS IN THE UNITED STATESJanice M. Reichert

The process of clinical development and regulatory review of new therapeutics in the UnitedStates was significantly changed by a number of legislative acts passed in the 1980s and 1990s.These acts were designed to encourage the development of innovative products, especially forrare, serious or life-threatening diseases, and to ensure that patients had timely access to thesetreatments. To assess the effects of the various modifications to the process, the Tufts Center forthe Study of Drug Development analysed clinical development and approval data for 554 thera-peutics (504 small molecules, 40 recombinant proteins and 10 monoclonal antibodies) approvedin the United States from 1980–2001. Trends in the number of approved products and the clinicaldevelopment and approval times indicated that the effects of these changes were generally bene-ficial as of the mid- to late-1990s, but that the gains have not been sustained in the early 2000s.Current efforts by the FDA, and the pharmaceutical and biopharmaceutical industry, to reversethe recent tendency toward fewer new approvals and longer approval times are discussed.

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Tufts Center for the Study of Drug Development,192 South Street, Suite 550,Boston, Massachussets02111, USA.e-mail:janice.reichert@tufts.edudoi:10.1038/nrd1178

A G U I D E TO D R U G D I S C O V E R Y

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they can be approved with restrictions to assure safe use.For products approved on the basis of surrogate end-points, the FDA can require well-controlled post-marketing studies to verify the efficacy of the therapeuticin the target patient population. Drugs given restrictedapprovals under the accelerated approval provisions forsafety reasons include thalidomide (Thalomid; Celgene— approved as a treatment for erythema nodosumleprosum, a complication of leprosy) and mifepristone(Mifeprex; Population Council — approved for themedical termination of intrauterine pregnancy).

Fast-track designation, which is separate and dis-tinct from priority review, can be conferred on therapeu-tics that are intended to treat serious or life-threateningconditions and which demonstrate the potential toaddress unmet medical needs. Benefits of the fast-trackprogramme include an emphasis on close and earlycommunication between the FDA and sponsors, and‘rolling’ submission of applications to the FDA (sub-mission of sections of the application over a specifiedperiod of time). Fast-track designation thereby pro-vides a potential benefit through the entire process ofdevelopment and approval5. Products with fast-trackdesignation are eligible for priority review, which isgiven to products that are potentially significantimprovements in the treatment of diseases. The poten-tial benefit of the priority review occurs in the approvalphase because the FDA expedites review of the marketingapplications for priority products.

The reductions in the approval times for therapeuticsthat have occurred during the past decade can be attrib-uted to performance goals that the FDA accepted as partof the PDUFA and FDAMA legislation6. These goalsincluded a first action phase of 12 months for a percent-age of all original applications submitted to the FDA in a

The Hatch–Waxman Act fostered innovation in thepharmaceutical and biopharmaceutical industries byrestoring patent terms that were lost during the process ofclinical development and approval of new therapeutics.The act allowed patent-life extension equal to half theclinical phase and the entire review phase, the sum ofwhich could not exceed five years. Moreover, theHatch–Waxman Act also promoted competition in mar-kets dominated by older therapeutics by defining require-ments for an abbreviated new drug application (ANDA),which significantly reduced the clinical data needed togain approval for a generic drug. The ANDA procedurecould, in theory, be used to market a generic versionimmediately after the patent for a new drug expired4. It isimportant to note that the ANDA process defined in theHatch–Waxman Act can be applied to therapeuticsapproved under the Food, Drug, and Cosmetic Act only,and therefore cannot affect biopharmaceuticals approvedunder the Public Health Service Act.

Further progress was made during the 1990s, whentwo legislative acts that introduced specific mechanismsintended to accelerate access to innovative therapeuticsand reduce approval times were signed into law: thePrescription Drug User Fee Act of 1992 (PDUFA) andthe Food and Drug Administration Modernization Actof 1997 (FDAMA). Accelerated approval, implementedin 1993 and codified in the FDAMA, and fast-trackdesignation, a provision of the FDAMA, are bothmechanisms used by the FDA to facilitate the develop-ment of therapeutics that are treatments for serious orlife-threatening diseases.

Products that provide a significant benefit over exist-ing therapies can receive accelerated approval on thebasis of a surrogate endpoint or on an effect on a clinicalendpoint other than survival or irreversible morbidity, or

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This review provides analyses of therapeuticsapproved in the United States during the past twodecades and an assessment of the effects of the variouslegislative acts on the process of clinical developmentand approval of these products. Small-molecule, recom-binant protein and monoclonal antibody therapeuticsare considered separately, and analyses are presented fordata stratified by several therapeutic categories and des-ignations (for example, orphan, accelerated approval,fast-track or priority review). These analyses provide abasis for evaluating on-going and future efforts by theFDA and the pharmaceutical and biopharmaceuticalindustry to improve access to innovative therapeuticsand accelerate the development and approval of newtherapeutic products.

Analysis criteriaThe Tufts Center for the Study of Drug Developmentcollected clinical development and regulatory reviewdata for 554 new therapeutics approved for marketingin the United States between 1980–2001 from companysurveys and public documents. Of these therapeutics,504 were small molecules, 40 were recombinant pro-teins (rDNA) and 10 were monoclonal antibodies(mAb). New small-molecule drugs (SMDs) weredefined as any novel molecular compounds reviewed byCDER that were neither proteins (recombinant or bio-logical) nor mAbs, and which had not been previouslyapproved in the United States. SMDs comprised 99% ofthe new chemical entities (NCEs; novel molecular com-pounds reviewed by CDER, including protein and mAbtherapeutics) approved from 1980–89, and 95% of theNCEs approved from 1990–2001.

New rDNA and mAb therapeutics were defined asunique proteins that received the first US approval forany therapeutic indication — that is, if the generic

given fiscal year (FY; October 1 to September 31) start-ing in 1994 (55% in FY 1994, 70% in FY 1995 and 80%in FY 1996). In FY 1997, separate goals for the firstaction phase were applied to therapeutics given stan-dard review (twelve months for 90% of original appli-cations) and priority review (six months for 90% oforiginal applications).

The next decade will bring a continued focus onaccess to new therapeutics and FDA performance.Orphan drug development might receive renewed atten-tion from the pharmaceutical and biopharmaceuticalindustries due to passage of the Rare Diseases Act andthe Rare Diseases Orphan Product Development Act inNovember 2002. These legislative acts increase fundingfor the Office of Rare Diseases (ORD) at the NIH andthe FDA’s Orphan Products Research Grant programme.The Prescription Drug User Fee Amendments of 2002(also known as PDUFA III), which were included in thePublic Health Security and Bioterrorism Preparednessand Response Act of 2002, contained performance goalsfor the FDA. The goals were maintained at the 2002 levelunder PDUFA III — that is, the FDA will review and acton 90% of standard original applications within tenmonths of receipt, and on 90% of priority originalapplications within six months.

Additional changes will occur at the FDA as respon-sibility for the review of therapeutic biopharmaceuticalsis transferred from the Center for Biologics Evaluationand Research (CBER) to the Center for Drug Evaluationand Research (CDER), and a risk-based approach tocurrent good manufacturing practice (cGMP) is imple-mented. The review of products by therapeutic cate-gory, rather than by type of product — that is, drug orbiological — might result in increased consistency ofreviews, whereas the cGMP initiative should encourageinnovation in manufacturing methods.

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Figure 2 | Mean clinical and approval phase lengths for small-molecule drugs approved in the United States during1970–2001.

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BIOLOGICS LICENSE APPLICATIONS (BLAs; reviewed by theCBER), PREMARKET APPROVAL APPLICATIONS (PMAs; reviewedby the CDRH) or Product License Applications (PLAs;precursor to BLA). For SMD, rDNA and mAb products,the approval phase was defined as the time from the dateof first application submission to the date the FDA firstapproved marketing of the product. The total was thesum of the clinical and approval phases.

The clinical phase for rDNA and mAb therapeuticswas defined somewhat differently than that for SMDsbecause a significant number (16%) were first studied inhumans prior to the product’s IND filing date. In thesecases, the first clinical study was done outside the UnitedStates; for one product, none of the clinical studies initi-ated before approval were done under a US IND. Onaverage, the products entered clinical studies 29 months(median of 21 months) prior to the IND filing. Becausean accurate clinical phase would not be calculated usingthe IND filing date in these cases, the date of the firstadministration to humans was substituted as the start ofthe clinical phase.

Numbers of new therapeuticsA total of 554 new SMD, rDNA and mAb therapeuticswere approved from 1980–2001 (FIG. 1). SMDs com-prised the majority of therapeutics approved each year.The number of SMDs approved per year was in therange of 11–28 products during most of the 22-yearperiod. The 1996–99 interval, during which the FDAapproved a total of 138 SMDs, was exceptional. There isa trend in recent years towards a smaller numbers ofSMD approvals per year, but this is relative to 1996–99.In 2000, 2001 and 2002, there were 23, 22 and 16 SMDapprovals, respectively. These numbers are within therange observed for all years but 1996, 1997 and 1999. Onthe basis of the number of yearly approvals, the 1990swere more productive than the 1980s. In five of the tenyears comprising the 1980s, the number of approvalsper year was 21 or fewer. By contrast, the number ofapprovals was 21 or fewer in only two years of the 1990s.

Therapeutic rDNA and mAbs have historically com-prised a relatively small number of the new therapeuticsapproved by the FDA, although these products haveslowly increased in number since the first rDNA productwas approved in 1982. Therapeutic rDNA and mAbscomprised 0–10% of the total number of approvalsduring 1980–1996, with the exception of 1986 when theyrepresented 15%. Interestingly, fluctuations in thepercentages were apparent when the value was calculatedfor 1997–2002. Whereas only 6% of approved therapeu-tics were rDNA and mAb in 1999, this figure was 19% in1997, 21% in both 1998 and 2000, 24% in 2001, and 30%in 2002. The increase in the percentages during 2000–02was due to two factors: the combined number of rDNAand mAbs approved yearly remained in the range of 6–7products, and the number of SMDs approvals fell backinto the range (11–28) observed for most years.

Clinical and approval phase lengths for SMDsClinical and approval phases were calculated for SMDsapproved in two-year intervals from 1980–2001. Zero or

name was identical to a previously approved therapeu-tic, then the product was not considered new. A total of48 rDNA7 and 10 mAb8 therapeutics were approved inthe United States during 1982–2001. Eight7 of the rDNAtherapeutics did not fit the definition of new, and so werenot included in any category. Therapeutic rDNA andmAb products, and a device containing an rDNAtherapeutic, were reviewed at either the CDER, CBER,Center for Devices and Radiological Health (CDRH),or, if approved before 1988, Center for Drugs andBiologics at the FDA. Diagnostic agents, vaccines andvariants of existing products (for example, new salt,ester, dosage, formulation, or form of delivery of pre-viously approved compounds) were excluded.

Data were stratified by year of approval, therapeuticcategory and FDA designation for the calculation of theclinical development period (CLINICAL PHASES I, II and III),the regulatory review period (approval phase; total ofFDA-review and sponsor-response time), and the totaltime from the start of clinical testing to approval (total).Therapeutic category was assigned on the basis of theproduct’s first approved indication. No analysis was donefor any cohort that included fewer than three products.

For SMDs, the clinical phase was defined as the timefrom the date of INVESTIGATIONAL NEW DRUG APPLICATION

(IND) filing to the date of NEW DRUG APPLICATION (NDA)submission. For rDNA and mAbs, the clinical phase wasdefined as the time from initiation of clinical studies(earliest of either the IND filing date, or the date ofthe first administration to humans) to the date that theappropriate marketing application was submitted tothe FDA; this includes NDAs (reviewed by the CDER),

CLINICAL PHASE I

Studies performed in a smallnumber of patients or normalvolunteers to evaluatepharmacokinetic properties(absorption, distribution,metabolism and excretion inhumans) and establish a safedosage range.

CLINICAL PHASE II

Trials performed in a smallnumber of patients to evaluatethe safety and effectiveness of aproduct in comparison with astandard or control treatment.

CLINICAL PHASE III

Large trials performed inpatients to confirm safety,efficacy and optimal dosagerange of a product incomparison with a standard or control for treatment of thetargeted indication.

INVESTIGATIONAL NEW DRUG

APPLICATION

(IND). Document filed by adrug sponsor to notify the Foodand Drug Administration of itsintent to conduct clinical studiesin human subjects.

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Anti-infective (n = 102)*Anaesthetic/analgesic (n = 59)*

Cardiovascular (n = 107)*

Antineoplastic (n = 38)*

Central nervous system (n = 51)*

Figure 3 | Mean clinical phase lengths for small-molecule drugs in five therapeuticcategories approved during five time periods. *Total number of products in each therapeuticcategory approved during 1982–2001.

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Trends in phase lengths by therapeutic categoryNotable differences in the clinical phase lengths havebeen observed for various therapeutic categories ofNCEs approved from 1985–2001 (REFS 9–15). To deter-mine the scope and magnitude of these differences forSMDs, mean and median clinical phases were calculatedfor products approved in four-year intervals from1982–2001, stratified by five therapeutic categories. Aninsufficient number of SMDs were approved to calcu-late the values for shorter intervals or for all possibletherapeutic categories in four-year intervals.

The mean clinical phases for all five therapeuticcategories ranged from 53–86 months during1982–85 (FIG. 3). No consistent trend is observedbetween 1986–97, although the majority of the meanclinical phases cluster in small ranges during twointervals. For example, four of the five categories were in the 63–78-month range during 1990–93.Antineoplastic SMDs approved in this interval had alonger mean clinical phase; four out of nine productshad clinical phases longer than 120 months (10 years).Also, four of the five categories were in the 81–103-month range during 1994–97. Finally, the mean clini-cal phases for all five categories decreased during1998–2001 into the range of 46–85 months, whichwas nearly identical to the range calculated for the1982–85 interval.

Compared with the mean clinical phases, themedian values for the five therapeutic categoriesshowed similar trends (FIG. 4). The most notable differ-ences were a decrease in the magnitude of the mediancompared with mean values for antineoplastic SMDsapproved in 1990–93, and, for products approved dur-ing 1994–97, a shift in the range towards shorter valuesin which the ‘outlier’ was central nervous system (CNS),not anti-infective, SMDs. No single therapeutic categoryconsistently had either the longest or shortest mean ormedian clinical phase for all five intervals. Anti-infectiveSMDs were the most consistent, with either the first orsecond shortest mean clinical phase in four intervals,and the first or second shortest median clinical phase inall five intervals. In contrast, CNS SMDs had the long-est mean clinical phase in three intervals, and thelongest median clinical phase in four intervals.Interestingly, there was a decrease in both the meanand median clinical phases for all five therapeutic cate-gories in 1998–2001 compared with 1994–97.

Therapeutics approved 1982–2001An insufficient number of rDNA and mAb therapeu-tics were approved in any given therapeutic category todetermine trends over time for these products.However, comparisons of the mean and median clini-cal and approval phases for some categories of SMD,rDNA and mAb therapeutics were possible when valueswere calculated for products approved during theentire 1982–2001 period. Even after expanding the timeframe for approvals, the number of rDNA and mAbtherapeutics in each category was still small. Productswere approved in five ostensibly comparable therapeuticcategories (TABLE 1).

only a few rDNA or mAb therapeutics were approvedduring most of these intervals, so results are not shownfor these products. Between 1982–2001, the mean clinicalphase rose from 61.6 months to a high of 92.5 months in1994–95 (50% increase), but then fell to 63.9 months(FIG. 2). Mean clinical phase lengths were calculated forSMDs approved during the 1970s to provide a historicalcontext for this phenomenon. The calculated valuesshowed a similar trend for products approved between1970–81 period; that is, the clinical phase rose from 39.3months in 1970–71 to a high of 65.3 months in 1976–77(66% increase), and then fell to 42.7 months in 1980–81.

In contrast to the fluctuations observed in the meanclinical phase, the mean approval phase remained rela-tively constant, and in the range of 23–37 monthsthrough the 1970s, 1980s and the early 1990s. Startingwith the 1994–95 interval, the approval phase began adownward trend which ended in the 2000–01 interval.PDUFA/FDAMA time-to-first-action performancegoals became effective in the FDA’s FY 1994 and sepa-rate performance goals were applied to standard andpriority review applications starting in FY 1997. Thepercentage of SMDs that received priority review ineach two-year interval from 1994–2001 was determinedin order to assess whether the percent of products thatwere priority reviewed might have affected the lengthof the approval phase. The percentages were 42% in1994–95, 30% in 1996–97, 52% in 1998–99, and 33%in 2000–01. For most of 1970–2001, the approval phasewas shorter and less variable than the clinical phase;therefore trends in the total SMD development andapproval time mirrored those for the clinical phase.

NEW DRUG APPLICATION,

BIOLOGICS LICENSE

APPLICATION, PREMARKET

APPROVAL APPLICATION

(NDA, BLA, PMA). Marketingapplications that contain theresults of clinical Phase I, II andIII studies and are submitted tothe FDA for review. If theapplications are approved, theproduct can be marketed in theUnited States.

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Figure 4 | Median clinical phase lengths for small-molecule drugs in five therapeuticcategories approved during five time periods. *Total number of products in each therapeuticcategory approved during 1982–2001.

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Anti-infective and antineoplastic SMDsTwo therapeutic categories of SMDs — anti-infectiveand antineoplastic — contained a sufficient number ofproducts for sub-categorization by inclusion in variousFDA programmes or designations (TABLES 2 and 3).

The anti-infective SMDs developed specifically astreatments for human immunodeficiency virus (HIV)infection had the shortest mean clinical phase (41.6months). These antiviral products comprised themajority of the anti-infective SMDs that received accel-erated approval (82%), and those that had fast-trackdesignation (83%). Clinical studies for priority-reviewed products — that is, those that were potentiallysignificant improvements in treatments for infectiousdiseases — took longer compared with products with astandard-review designation. Orphan products madeup only 13% of the total number of anti-infectives, andthe mean and median clinical phase was longer fororphan compared with non-orphan SMDs.

The approval-phase lengths for the anti-infectiveSMDs had an inverse relationship to the percentage ofproducts that were priority reviewed; that is, theapproval phase decreased as the percentage of priorityreviewed products in each category increased. TheHIV antiviral products, and the accelerated approvaland fast-track designated products, had mean approvalphases of less than seven months; applications forproducts submitted during or after FY 1992 were allpriority reviewed. Compared with the standard-reviewed products, the mean approval phase of priority-reviewed products was 50% shorter. Orphan productshad a 29% shorter mean approval phase comparedwith non-orphan SMDs; all applications for orphanSMDs submitted during or after FY 1992 were priorityreviewed, whereas this was the case for only 49% of thenon-orphans.

The mean and median clinical phase for SMDs wasmarkedly shorter than that for rDNA and mAb thera-peutics in only one category: anti-infective therapeu-tics. The majority of the anti-infective SMDs weretreatments for acute infections (for example, bacterial,fungal and helminthic infection), whereas the rDNAtherapeutics were for chronic indications (for example,hepatitis C and chronic granulomatous disease). Themean clinical phase for immunological SMDs wassimilar to that for rDNA products in the same cate-gory. The immunological SMDs, however, includethalidomide, which was studied as a sedative in theearly 1960s, and so was formally in clinical studies formore than 30 years. If this product is excluded, thenthe mean clinical phase for the immunological SMDcohort falls to 59.1 months (median 52.6), which isslightly faster (10%) compared with the mAb thera-peutics in the same category.

The mean approval phase lengths for four out of fivecategories of SMDs were relatively long (more than 18months) during the 1982–2001 period. One category —immunological SMDs — had notably short mean andmedian approval phases (9.8 and 8.4 months, respec-tively). NDAs for the majority (82%) were submittedduring or after the FDA’s FY 1994, when priorityreviews and performance goals were implemented;78% of these products were priority reviewed. Meanand median approval phases for rDNA and mAbs in alltherapeutic categories tended to be shorter than thosefor SMDs, though this was probably because the major-ity of rDNA and mAb therapeutics were approvedduring or after 1994. Antineoplastic mAbs had theshortest mean and median approval phases (9.2 and 7.8months, respectively). Applications for all four productswere priority reviewed with six month time-to-first-action performance goals.

Table 1 | Mean (median) phase lengths for five categories of therapeutics approved 1982–2001

Clinical phase (in months) Approval phase (in months) Total (in months)

Anti-infective

SMD (n =102) 55.8 (47.9) 18.6 (14.0) 74.5 (64.2)

rDNA (n = 3) 98.3 (85.2) 14.2 (12.9) 112.5 (98.1)

Antineoplastic

SMD (n = 38) 96.8 (81.6) 19.2 (12.8) 116.0 (101.0)

rDNA (n = 4) 46.6 (51.3) 27.6 (27.6) 74.2 (71.7)

mAb (n = 4) 80.7 (66.0) 9.2 (7.8) 89.9 (71.7)

Cardiovascular

SMD (n = 107) 73.1 (59.6) 30.2 (26.7) 103.3 (91.7)

rDNA (n = 4) 55.6 (59.5) 21.1 (17.3) 76.7 (72.5)

Endocrine

SMD (n = 36) 92.2 (75.2) 23.1 (14.9) 115.3 (95.9)

rDNA (n = 10) 51.9 (56.7) 17.1 (13.5) 69.0 (73.7)

Immunological

SMD (n = 11) 90.3 (63.6) 9.8 (8.4) 100.2 (67.7)

rDNA (n = 4) 92.1 (96.2) 13.3 (11.9) 105.4 (105.1)

mAb (n = 4) 65.4 (68.4) 11.6 (6.9) 77.0 (77.5)

mAB, monoclonal antibody; rDNA, recombinant protein; SMD, small-molecule drug.

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decades have been extraordinary, but the questionremains: have the changes made a difference? Theanswer would have been a resounding yes in the mid- tolate-1990s. The number of new products approved wasrising while both clinical development and approvaltimes were falling. Innovative therapeutics that met thestandards for accelerated approval, and fast-track andpriority-review designation — particularly in the fieldsof AIDS and cancer — were being developed andapproved quickly.

However, on the basis of the results seen so far in the2000s, the answer to the question would be a morequalified yes. From 2000–02, the rosy scenario deterio-rated as the number of original application submissionsand approvals for new therapeutics began to decrease.Moreover, approval times began increasing, in partbecause the number of priority-reviewed products,which are innovative treatments for disease and thosemost likely to be reviewed quickly, decreased.

Clearly, the situation prevailing in the mid- to late-1990s, which included both a high output of innovativeproducts and consistently fast reviews, was not a stablestate for either the industry or the FDA. Conditionsmight have changed for the worse in response to avariety of factors, including advances in technology,fluctuation in the investment of resources, and shifts in

For antineoplastic SMDs, the mean clinical phasefor products that received accelerated approval was43% shorter compared with that for all SMD antineo-plastics approved during 1982–2001. Priority-reviewedproducts had a slightly shorter (7%) mean, but a signif-icantly shorter (30%) median, clinical phase comparedwith the standard-reviewed products. Orphans were50% of the total number of antineoplastic SMDs;mean clinical phase was longer (40%) than that for thenon-orphans, but the respective median was onlymarginally longer (4%).

The approval phases for the antineoplastic SMDsfollowed the same trend as observed for the anti-infective products, in that categories containing highpercentages of priority-reviewed products had shortapproval phases. Compared with standard-reviewedproducts, the mean approval phase for priority-reviewed antineoplastic SMDs was 42% shorter. Themean approval phase for the orphan products was 28%shorter compared with that for the non-orphans; prior-ity-reviewed products comprised 83% of the orphanand 58% of the non-orphan antineoplastic SMDs.

Current state of affairsThe scope and degree of the changes to the process oftherapeutics development and review in the past two

Table 3 | Mean (median) phase lengths for antineoplastic SMDs approved during 1982–2001

Clinical phase Approval phase Total(in months) (in months) (in months)

Antineoplastics approved 1982–2001 (n = 38) 96.8 (81.6) 19.2 (12.8) 116.0 (101.0)

Accelerated approval (n = 7) 54.8 (52.6) 14.2 (11.9) 69.0 (67.8)

Priority review* (n = 17) 77.4 (62.5) 11.8 (8.8) 89.2 (72.0)

Standard review* (n = 7) 83.3 (88.8) 20.5 (12.6) 103.8 (104.5)

Orphan (n = 19) 113.1 (83.8) 16.0 (12.7) 129.1 (103.3)

Non-orphan (n = 19) 80.6 (80.7) 22.3 (15.4) 102.9 (88.8)

Antineoplastics approved 1998–2001 (n = 9) 75.4 (55.9) 7.6 (8.2) 83.1 (67.8)

*Priority and standard review designations were assigned starting in 1992; antineoplastic small-molecule drugs (SMDs) approved during1982–91 had the following review ratings: A (8 products), B (3 products), C (3 products). SMDs thought to represent a significant gain, amodest gain, or little to no gain over existing therapy were assigned A, B or C ratings, respectively9.

Table 2 | Mean (median) phase lengths for anti-infective SMDs approved during 1982–2001

Clinical phase Approval phase Total(in months) (in months) (in months)

Anti-infectives approved 1982–2001 (n = 102) 55.8 (47.9) 18.6 (14.0) 74.5 (64.2)

Antivirals, HIV (n = 16) 41.6 (43.3) 4.6 (4.1) 46.2 (48.8)

Accelerated approval, HIV (n = 14) 43.9 (44.1) 4.6 (4.1) 48.5 (51.4)

Accelerated approval (n = 17) 46.4 (48.5) 6.9 (5.8) 53.2 (52.9)

Fast track (n = 6) 47.1 (46.8) 5.0 (5.8) 52.2 (52.7)

Priority review* (n = 29) 67.5 (53.8) 9.8 (6.0) 77.4 (59.1)

Standard review* (n = 23) 50.2 (47.9) 19.4 (16.3) 69.6 (65.5)

Orphan (n = 13) 87.5 (66.3) 13.7 (7.6) 101.9 (75.7)

Non-orphan (n = 89) 51.5 (46.6) 19.3 (16.3) 70.8 (64.2)

Anti-infectives approved 1998–2001 (n = 16) 46.4 (47.7) 8.8 (6.0) 55.3 (53.6)

*Priority and standard review designations were assigned starting in 1992; anti-infective small-molecule drugs (SMDs) approved during1982–91 had the following review ratings: A (10 products), B (14 products), C (26 products). SMDs thought to represent a significantgain, a modest gain, or little to no gain over existing therapy were assigned A, B or C ratings, respectively9.

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the market by enhancing industry practices in key areas,such as managing portfolios, projects, and alliances,establishing industry-wide standards for use of elec-tronic technology, and capitalizing on scientific discov-eries. A renewed focus on rDNA and mAb therapeuticsmight improve the yield of innovative products. Thepotential of these products is just beginning to be real-ized: the majority of the rDNA and mAb therapeuticsmarketed in the United States were approved in the lastsix years7,8. Therapeutic rDNA and mAb products aregenerally complementary to, not competitive with,SMDs because they are larger, more complex molecules,and therefore might have modes of action that cannotbe reproduced by SMDs. Moreover, the average clinicaldevelopment phases for rDNA and mAb products infour therapeutic categories — antineoplastic, cardiovas-cular, endocrine and immunological — are similar toor faster than those for SMDs.

The current efforts by the FDA to facilitate theprocess of therapeutics development and approval, andby the industry to reduce inefficiency, are not a panacea.However, the FDA initiatives and industry strategies canaugment the existing legislative acts in encouraging thedevelopment of innovative therapeutics, and mightdecrease the time to market. The ultimate goal of boththe FDA and industry is to provide patients with accessto new, safe and effective treatments. Coordination andcooperation between industry and FDA will be requiredto meet this goal.

the national and international business and regulatoryenvironments. The effects of some of these variablesmight not be observed for years though, so the currentdownturn could be due in part to conditions that pre-vailed five to ten years ago.

Strategies for improvement in the futureFDA initiatives and industry strategies to address someof the current problems are being implemented. Forexample, the FDA has pledged to assist industry in thepreparation of high-quality applications as a way todecrease the need for multiple review cycles. This assis-tance will include close communication with sponsorsthroughout the development and approval process,collaboration with industry to identify common issuesconcerning the design and execution of clinical studies,and better guidances for sponsors developing oncology,diabetes and obesity therapeutics, or applying emergingtechnologies, such as cell and gene therapy, pharmaco-genomics and novel drug delivery systems16. In addition,the FDA is renewing efforts to facilitate the developmentof treatments for serious and life-threatening diseases,and is collaborating with the National Cancer Instituteon basic and clinical research in oncology.

The FDA can only assist in the process though. Thedevelopment of innovative products is actually accom-plished by the pharmaceutical and biopharmaceuticalindustry. The industry can improve the output of newtherapeutics and the speed with which drugs make it to

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5. Milne, C.-P. & Bergman, E. Fast track product designationunder the Food and Drug Administration Modernization Act:the industry experience. Drug Inf. J. 35, 71–83 (2001).

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7. Reichert, J. M. & Paquette, C. Therapeutic recombinantproteins: trends in US approvals 1982–2002. Curr. Opin.Mol. Ther. 5, 139–147 (2003).

8. Reichert, J. M. Therapeutic monoclonal antibodies: trends indevelopment and approval in the US. Curr. Opin. Mol. Ther.4, 110–118 (2002).

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10. Kaitin, K. I. & Cairns, C. The new drug approvals of 1999,2000, and 2001: drug development trends a decade afterpassage of the user fee act. Drug Inf. J. (in the press).

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14. Kaitin, K. I., DiCerbo, P. A. & Lasagna, L. The new drugapprovals of 1987, 1988, and 1989: trends in drugdevelopment. J. Clin. Pharmacol. 31, 116–122 (1991).

15. Kaitin, K. I., Richard, B. W. & Lasagna, L. Trends in drugdevelopment: the 1985–86 new drug approvals. J. Clin.Pharmacol. 27, 542–548 (1987).

16. US FDA. Improving Innovation in Medical Technology:Beyond 2002 [online], (cited 04 August 2003),<http://www.fda.gov/bbs/topics/news/2003/beyond2002/report.html> (2002).

AcknowledgementsThe author gratefully acknowledges the work of Elaine Bergman,Catherine Cairns and Cherie Paquette in maintaining the marketednew chemical entity and biopharmaceutical databases, and thanksDrs Kenneth Kaitin and Joseph DiMasi for helpful comments andsuggestions.

Online links

FURTHER INFORMATIONCenter for Biologics Evaluation and Research:http://www.fda.gov/cber/Center for Devices and Radiological Health:http://www.fda.gov/cdrh/Center for Drug Evaluation and Research:http://www.fda.gov/cder/Access to this interactive links box is free online.