rare cancer trial design: lessons from fda approvals · published onlinefirst june 20, 2012; doi:...

CCR Perspectives in Drug Approval

Rare Cancer Trial Design: Lessons from FDA Approvals

Himabindu Gaddipati1, Ke Liu2, Anne Pariser3, and Richard Pazdur2

AbstractA systematic analysis of clinical trials supporting rare cancer drug approvals may identify concepts and

terms that can inform the effective design of prospective clinical trials for rare cancers. In this article, using

annual incidence �6 of 100,000 individuals to define "rare cancer," we identified clinical trials for rare

cancers, supporting U.S. Food and Drug Administration (FDA) drug approvals for rare cancer indications

between December 1987 and May 2011. We characterized each selected trial for study design, sample size,

primary efficacy endpoints, and statistical comparisons. We also profiled trials with regard to type of

submission, review designation, and approval type. Our results indicated that, of 99 trials that supported

the approvals of 45 drugs for 68 rare cancer indications, one third of these trials were randomized; 69% of

approvals relied on objective response rate as the primary efficacy endpoint; and 63%were based on a single

trial. Drugs granted accelerated approval appeared more likely to be associated with postmarketing safety

findings, relative to drugs approved under the regular approval. Data collected across clinical trials were

robust: Use of different lower incidence rates in analyzing these trials did not have effects on trial

characteristics. The absolute number of drug approvals for rare cancer indications increased markedly over

time. We concluded that one third of clinical trials supporting drug approvals for rare cancer indications

were randomized, affirming the feasibility and value of randomized trial design to evaluate drugs for rare

cancers. Postmarketing safety datamay relate to trial design and approval type. An operational definition of

"rare cancer" canbe useful for the analysis of trial data and for the path towardharmonizing the terminology

in the area of clinical research on rare cancers. Clin Cancer Res; 18(19); 5172–8. �2012 AACR.

IntroductionRare cancers are rare diseases and pose particular chal-

lenges to programs of drug development. By definition, therelevant patient populations are geographically dispersed,and the paucity of patients is frequently exacerbated bylimited access to experienced oncologists who specialize inthese cancers. Rare cancers are further problematic owing totheir poorly understood natural histories, their phenotypicheterogeneity, and to a range of manifestations that, evenwithin a given phenotype, can be diverse. Rare cancers thusrepresent a particular unmet need in clinical oncology.

The U.S. Food and Drug Administration (FDA) has rec-ognized the importance of addressing unmet needs by

instituting programs to facilitate the research, development,regulation, and approval of therapeutic agents for rare dis-orders and seriousdiseases.One such initiative is theOrphanDrug Act (ODA), which provides incentives to make thedevelopment of drugs for patients with orphan diseasesfinancially viable (1). The Secretary of Health and HumanServices designates an orphan disease as a condition thataffects less than 200,000 persons in theUnited States (or onethat affects >200,000 people, but where there is "no reason-able expectation that the cost of development" of the drugwill be recovered from sales in the United States; ref. 2).Under the ODA, orphan disease designation qualifies thedrug’s sponsor for 7 years of market exclusivity (3), certaintax credits (4), andwaiverof fees thatotherwisewouldbedueunder the Prescription Drug User Fee Act (PDUFA; ref. 5).

The approval of an orphan designation request, however,does not obviate existing legal and regulatory requirementsfor drug approval (6). Accordingly, the safety and effective-ness of the orphan product must be established, beforemarket approval, through adequate and well-controlledstudies (4). In addition, the FDA maintains initiatives suchas fast-track drug development, priority review, and accel-erated approval. (See Supplementary Textbox for definitionsof selected regulatory terms). Furthermore, the FDA’s Centerfor Drug Evaluation and Research (CDER) has recentlyestablished a rare diseases program to facilitate and supportthe research, development, regulation, andapprovalofdrugsand biologic products for the treatment of rare disorders (7).

Authors' Affiliations: 1Food and Drug Administration (FDA)-NationalCancer Institute Interagency Oncology Task Force, 2Office of Hematologyand Oncology Products, Office of New Drugs (OND), Center for DrugEvaluation and Research (CDER), and 3OND, CDER, FDA, Silver Spring,Maryland

Note: Supplementary data for this article are available at Clinical CancerResearch Online (http://clincancerres.aacrjournals.org/).

H. Gaddipati is currently not affiliated with any institution.

Corresponding Author: Ke Liu, Office of Hematology and OncologyProducts, Office of New Drugs, Center for Drug Evaluation and Research,FDA, 1401 Rockville Pike, HFM-760, Rockville, MD 20852. Phone: 301-827-9084; Fax: 301-827-0910; E-mail: [email protected]

doi: 10.1158/1078-0432.CCR-12-1135

�2012 American Association for Cancer Research.

ClinicalCancer

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The challenges of conducting clinical trials to investigatedrugs for rare cancers include the appropriate use of end-points. Oncology trials are often designed using surrogateendpoints, such as overall tumor response rate, which arenot necessarily direct metrics of survival or irreversiblemorbidity. The accelerated approval (AA) regulation wasestablished so that the unmet medical needs could beaddressed through the use of surrogate endpoints that arereasonably likely to predict clinical benefit (8, 9). Sponsorsof drugs granted accelerated approval are required to con-duct postapproval clinical trials to verify clinical benefit andthereby prevent the drug from being removed from themarket (10, 11).Under the current version of 21 C.F.R. 316.20(b)(6),

orphan drug designation may also be granted for a drugintended for a narrow indication, encompassing a specific,medically plausible disease subset or "orphan subset" (12).FDA has recently proposed a rule that would clarify thisportion of the regulation (12). One ramification of thisproposed rule, should it become final, could be that com-mon cancers may comprise subsets which, by virtue ofexpressing specific molecular markers, could becomeorphan subsets. For example, tumors of 4% to 7% patientswith non–small cell lung cancer (NSCLC; a common can-cer) overexpress anaplastic lymphoma kinase (ALK; refs. 13,14). The drug crizotinib has been specifically developed forpatients with ALK-positive tumors and was granted orphanstatus.In the absence of a clear definition for "rare" cancers,

regulatory recommendations with regard to drug develop-ment can be problematic, as evidenced in 2011 at anOncologicDrugAdvisoryCommittee (ODAC)meeting thatfocused on the discussion of potential trial designs for theconsideration of accelerated approval for oncologic drugs(15). Although committeemembers agreed that acceleratedapprovals of oncology products in general would be betterserved through randomized trials, rather than single-armtrials, they commented that owing to challenges of patientrecruitment in rare disease trials, single-arm trials might beconsidered for trials involving rare cancers. However, areasonable working definition for a rare cancer has yet tobe established. These and many other discussions havesuggested to us that stakeholders in drug development—particularly, those who are tasked with the design of pro-spective trials in oncology—might benefit from a systematicanalysis of clinical trials that have led to the approval ofdrugs for the treatment of rare cancers.Here, we report a retrospective analysis of FDA drug

approvals associated with rare cancers, according to ouroperational definition of 6 cases per 100,000 persons peryear.We relied on FDA internal databases pertaining to trialdata, collected between December 1987 and May 2011, asdescribed below.

Materials and MethodsFigure 1 outlines the steps used in generating the database

for our analyses, pertaining to 45 drugs for 68 approved rare

cancer indications that were supported by a total of 99trials (Supplementary Table S1). The information inthis database was independently verified by 4 FDA staffmembers from the Office of Hematology and OncologyProducts (OHOP), Office of New Drugs (OND), CDERwho were not associated with this research. For purposesof our analysis, we define "rare cancer" by an incidencerate of �6 new cases per population of 100,000 per year.This incidence rate was first suggested by the Surveillanceof Rare Cancers in Europe project (funded by the Euro-pean Commission; ref. 16), based on the assumption thatit would be difficult to conduct a randomized trial belowthis threshold. This definition would predict approxi-mately 18,000 new patients per year in the United States,based on recent U.S. population census data (�308million in 2010). According to this criterion, we estimat-ed the incidence rate for any given selected indication onthe basis of the published information from the Surveil-lance, Epidemiology and End Results program of theNational Cancer Institute (17), the National Comprehen-sive Cancer Network (18), and UpToDate (19). It shouldbe noted that incidence rates for specific cancer stages aregenerally not available, so that any given indication usedin our analyses stands without regard for cancer stage. Forexample, in April 2011, vandetanib was approved forpatients with symptomatic or progressive medullarythyroid cancer, a subset of patients with unresectablelocally advanced or metastatic disease. Because the annu-al incidence of this subset is unknown, we estimated theincidence rate for vandetanib’s indication at 2,000 casesper 100,000 per year on the basis of all stages of med-ullary thyroid cancer instead of the subset of symptomaticor progressive medullary thyroid cancer. However, oneexception to this rule is the incidence of non–Hodgkinlymphoma (NHL), in which the incidence rate was esti-mated on the basis of the subtypes. Although as a whole,the incidence for NHL is greater than 6 per 100,000per year, NHL subtypes represent clinically distinct dis-eases with respect to their biology, natural history, andtreatment.

For each of the 68 rare cancer indications, we analyzedthe characteristics of the corresponding trial(s) that sup-ported the indication’s approval in terms of the numberof trials conducted, study design, sample size, primaryefficacy endpoints, and statistical analysis. We alsotracked whether approval was accelerated or regular,whether the approved product was a new molecular entity(NME), proposed mechanism of action, approval date,and whether the review type was priority review or stan-dard review. For drugs granted accelerated approval, thestatus of their postmarketing commitments was alsoreviewed, and we ascertained whether any importantpostmarketing safety findings resulted in the revision ofthe "Warnings and Precautions" section of the productpackage insert.

The statistics we present throughout our retrospectiveanalyses of the trials are descriptive and not hypothesisdriven.


www.aacrjournals.org Clin Cancer Res; 18(19) October 1, 2012 5173




ResultsBetween December 1987 and May 2011, a total of 45

oncology products were approved for 68 rare cancer indica-tions (i.e., incidence rates �6 per 100,000 per year; seeSupplementary Table S1). Thirty-three drugswere approvedfor a single indication each; 8 were approved for 2 indica-tions; one drugwas approved for 3 indications; 2 drugswereapproved for 4 indications; and one drug, imatinib, wasapproved for a total of 8 different indications.

Over the time period inspected, there was a markedincrease in number of indications approved for rare cancers(Fig. 2B). Whereas 7 new indications were approved in thetime leading up to 1993, 33 new indications were approvedfrom 2006 to 2011. Forty-eight of the 68 indications (70%)were approved for hematologic malignancies (Fig. 2A), 37(54%) for NMEs, and 28 (41%) as efficacy supplements fornew indications, one (1%) for a new formulation of anexisting drug, and 2 (3%) for newmanufacturing methods.

Trial design and endpointsOf the total 99 trials involved in our analysis of FDA-

approved rare cancer indications, one third were random-ized controlled (Fig. 3A). Of these 33 randomized trials,32 were multicenter trials and 15 were blinded in somefashion: 12 were double blinded (6 placebo-controlledtrials and 6 controlled by active comparator), and 3 weresingle blinded. The remaining 18 randomized trials wereopen label. The most common primary efficacy endpoint,used for 69% of the approvals, was overall objective

response rate (ORR; complete and partial responses); thehigh use of ORR correlates with the preponderance ofsingle-arm design among the trials. Less frequently usedendpoints included time to progression (TTP; 7%), pro-gression-free survival (PFS; 10%), and overall survival (OS;6%; Fig. 3C).

Number of trials and trial sizeThe average number of trials conducted per indication

was 1.5 (99 trials for 68 rare cancer indications). Only 25indications (37%) were approved on the basis of the resultsfrom more than one trial: 20 indications from 2 clinicaltrials; 4 indications from 3 trials; and one indication from 4small trials in aggregate. The mean sample size was 174patients with a median of 94 patients (range, 5–846patients). For the 66 single-arm trials, median sample sizewas 54 patients; among the 33 randomized trials, themedian sample size was 301 patients.

Regulatory characteristics and postmarketing safetyissues

Themajority of the 68 indications (60%; see Supplemen-tary Table S1) were granted after a priority review, typicallywithin 6months of submission (Fig. 3B); of the indicationsreviewed after 1992,when standard andpriority review tierswere established under the PDUFA (20), the fraction ofpriority reviews is 64%. Twenty-four of the 68 indications(35%)were granted through accelerated approval (Fig. 3D);of the indications approved after introduction of theaccelerated approval regulation in 1992 (20), 37% were

© 2012 American Association for Cancer Research

FDA internal database (1987–2009)

120 approved oncology orphan indications

(85 Drugs)

Incidence rate > 6/100,000/year and

benign or supportive care indications?

NoYes

Exclude 54 approved rare cancer

indications (42 drugs)

68 approved rare cancer indications

(45 drugs) Supported by 99 trials

Analyze for trial

characteristics and profiles

FDA data (2005–2011)

10 approved rare cancer

indications (supplemental)

(8 existing drugs)

+

4 approved rare cancer

indications (3 new drugs)

Figure 1. A flowchart showingthe derived number of clinicaltrials supporting the drugapproval for rare cancerindications from December1987 toMay 2011. FromanFDAinternal database whichcontained 85 drugs for 120oncology orphan indicationsapproved from December 1987to December 2009, weexcluded benign hematologicand supportive care conditionsand indications for diseaseswith an incidence rate >6 per100,000 per year to generate alist that contained 42 drugs for54 rare cancer indications (left).To this list, we added 10 rarecancer indications (efficacysupplements from 8 drugs) and3 new drugs for 4 rare cancerindications, approved fromJanuary 2005 to May 2011,which were not included in theinitial FDA internal database(right). The resulting rare cancerapproval list was composed of45 products for 68 oncologyindications that were supportedby 99 trials (second box frombottom; see SupplementaryTable S1 for the list).

Gaddipati et al.

Clin Cancer Res; 18(19) October 1, 2012 Clinical Cancer Research5174




approved under accelerated approval. Of the 24 indicationsgranted accelerated approval, 11 (46%) have completedpostmarketing commitments to date.Postmarketing safety issues related to the approved rare

cancer products are tabulated in Supplementary Table S2.Only one drug, gemtuzumab, initially approved for thetreatment of elderly patients with acute myeloid leukemia,was removed from the market in June 2010 due to unac-ceptable toxicity, mortality, and lack of clinical benefit (21).Of the 19 products granted accelerated approval for 24

indications, 8 products (42%) were associated with newimportant toxicity findings identified from the postmarket-

ing experience and led to a revision of the "Warning andPrecautions" section of the product labeling. In contrast, 7(27%) of 26 products that were given regular approvalfor 44 indications had postmarketing toxicity issues. Indi-cations approved through accelerated approval were lesslikely tohave reliedupon randomized trial design thanwerethose indications approved through regular approval (21%vs. 43%, respectively). Trials associated with acceleratedapproval were also less likely to depend on endpoints ofPFS, TTP, and symptomatic improvement (SI) or OSthan were the trials that supported the regular approval(13% vs. 35%, respectively).

Figure 2. FDA approvals for 68rare cancer indications. A,approvals by tumor type asshown. B, approvals by timeperiods as shown.


Endocrine (3)

Gastrointestinal (2)

Genitourinary (1)

Hematologic (48)

Neurologic (6)

Sarcoma (3)

Miscellaneous (5)

30

20

10

1987–1993

7

11

17

33

B

A

1994–1999 2000–2005 2006–2011

Time period

Num

ber

of

app

rove

d in

dic

atio

ns

40






Characterization of trials as a function of incidencerate for defining rare cancers

To explore whether our choice of incidence rate (�6 per100,000 per year) in selecting data might have biasedassessment of the feasibility and value of conducting ran-domized controlled clinical trials, we further characterizedtrials as a function of incidence rate. By applying arbitraryincidence rates of�1,�2,�3,�4,�5, and�6new cases per100,000 per year to our trial data, wewere able to determinewhether the selected incidence rate had any effect on trialcharacteristics such as median sample size, percentage ofrandomized trials, and use of response rate as primaryendpoint. As shown in Table 1, the choice of different lowerincidence rates for analyzing the 99 trials had no apparenteffect upon these trial characteristics.

Discussion

The importance of applying effective trial design is espe-cially underscored in the context of rare diseases. In partic-ular, recent discussions have questioned the practicality ofapplying randomized trial designs to evaluations of rareconditions (22, 23). We undertook the present study tooffer a comprehensive analysis of drug approvals specifi-cally in the context of rare cancer.

The primary goal of the analysis presented here is toprovide heuristic profiles of those clinical trials that havesupported FDAdrug approvals for rare cancer.Wehope thatsuch profiles will prove useful to stakeholders involved in

various aspects of drug development and drug approval.Specifically, we have analyzed the characteristics of 99clinical trials that supported the approval of 45 products,between December 1987 and May 2011, for 68 indicationsof "rare" cancer, defined by an incidence threshold of nomore than 6 new cases per 100,000 people per year. Webelieve that this incidence threshold as an operationaldefinition can prove to be of value. Although this thresholdis not to be construed as an exact definition for a rare cancerand does not reflect a standard expressed by the FDA, weexpect that it can be of practical use for researchers in theanalysis of trial data and for the path toward harmonizingthe terminology in the area of clinical research on rarecancers.

One of 3 trials in our retrospective analysis proves tohave been randomized controlled (Fig. 3A). This consider-able proportion of randomized trials appears to be a rela-tively rigorous statistic; it does not appear to be a function ofthe specific threshold of incidence rate chosen for analysis(Table 1). It must be noted, however, that the small numberof clinical trials defined by any of the given thresholds ofincidence rate (Table 1) precludes highly rigorous hypoth-esis-driven statistical analyses. Nevertheless, our resultsclearly indicate that randomized controlled trials providefeasible avenues for evaluating the efficacy and safety oftherapeutics in many rare cancer indications. This findinghas important implications for sponsors as they considertrial design and invest in the development of drugs for rarecancer indications.


Randomized

5 (7%)1 (1%) 2 (3%)

4 (6%)

47 (69%)

2 (3%)7 (10%)

TTP TTE SI Survival ORR Reduced

toxicity

PFSSingle-arm

33 (33%)

66 (67%)

Standard Priority

23 (36%)

41 (64%)

Regular Accelerated

40 (63%)

24 (37%)

A C

B D

Figure 3. Characteristics ofclinical trials supporting the rarecancer drug approvals. A totalof 99 clinical trials supportedthe approval for 68 rare cancerindications. A, randomizedversus single-arm design. B,standard versus priority review.C, primary study endpoints. D,approval types: regular versusaccelerated approval. Priorityreview and acceleratedapproval in B and D wereapplicable after 1992 (see textfor details). SI, symptomaticimprovement; TTE, time toengraftment.

Gaddipati et al.





An additional finding in our study is that the productsthat were granted accelerated approval for rare cancersindications appear, relative to those approved under regularapproval, to manifest a higher incidence of postmarketingsafety issues (42% vs. 27%, respectively). It should bepointed out that accelerated approval drugs, like thoseapproved via the regular approval process, must still beshown to be safe; the difference in rates of postmarketingsafety issues usually becomes apparent only because amuch larger patient population is exposed to the givenproduct after its approval. In any event, the higher incidenceof postmarketing safety issues associated with productsapproved under accelerated approval is not surprising,given the fact that accelerated approval can be based onsmall sample sizes and endpoints other than survival orirreversible morbidity. It is for this reason that safety infor-mation, including OS, should be continuously assessedfollowing approval. In our analysis, 46% of rare cancerindications that had been granted accelerated approvalfulfilled their postmarketing commitments. This percentageappears to be lower than the 55% reported by Johnson andcolleagues for all oncology products that were grantedaccelerated approval and had fulfilled their postmarketingcommitments (24). The reason for this relatively smalldiscrepancy is unknown, although it may reflect the inher-ent challenges in conducting clinical trials for rare cancers(e.g., difficulty in adequate patient recruitment).It should be noted that of the 68 rare cancer indications

that we discuss here (see Supplementary Table S1), 43(63%) were based on results from a single pivotal trial.This result indicates FDA’s flexibility in making productsthat address unmet need available to patients as early aspossible. The reliance on the results from one trial forapproval is consistent with section 115(a) of the Foodand Drug Administration Modernization Act of 1997,which states that the Secretary of Health and HumanServices may consider "data from one adequate and wellcontrolled clinical investigation and confirmatory evi-dence" to constitute "substantial evidence" for purposesof subsections 505(d) and (e) of the Federal Food, Drug,and Cosmetics Act if the Secretary determines that suchdata and evidence are "sufficient to establish effective-ness" (25).

With respect to trial endpoints that supported theapprovals discussed here,ORRwas the primary efficacy end-point used for 69% of the approvals, which correlates withthe prevalence of single-arm design among the trials. In theremainder of the trials, OS, PFS, TTP, time to engraftment(TTE) and SI were generally used as primary endpoints,which is consistent with published FDA guidance that inthe randomized trial setting, time-to-event endpoints, ratherthan response rate, should be preferred endpoints (26).

We expect that the trend toward increasing numbers ofrare cancer drug approvals (Fig. 2B) will continue in theforeseeable future, especially given the improvements intarget identification that are underpinning cancer biology.As novel targets are identified, subsets of common cancersmay be defined as rare cancers according to their uniquemolecular profiles and meeting arbitrary criteria. Withsuccessful identification of molecular targets, the comingera of personalized medicine may thus usher in familiarchallenges, in terms of adequate patient recruitment, trialdesign, and choice of trial endpoints, that had previouslybeen associatedwith therapeutic approaches to rare cancers.Our continued commitment to foster disease awareness,advocacy, and research is crucial, as are our efforts toelucidate those trial design parameters uponwhich efficientdrug development will best flourish.

Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.

DisclaimerResults of this manuscript have not been previously presented or pub-

lished. The opinions expressed in this article do not necessarily reflectthose of the U.S. Food and Drug Administration and the U.S. government.

Authors' ContributionsConception and design: H. Gaddipati, K. Liu, A. PariserDevelopment of methodology: H. Gaddipati, K. LiuAcquisitionofdata (provided animals, acquired andmanagedpatients,provided facilities, etc.): H. Gaddipati, K. Liu, R. PazdurAnalysis and interpretation of data (e.g., statistical analysis, biosta-tistics, computational analysis): H. Gaddipati, K. LiuWriting, review, and/or revision of themanuscript:H. Gaddipati, K. Liu,A. Pariser, R. PazdurAdministrative, technical, or material support (i.e., reporting or orga-nizing data, constructing databases): H. Gaddipati, K. LiuStudy supervision: K. Liu

Table 1. Trial characteristics as a function of incidence rates

Incidence rate(number of newcases per 100,000per year)

Numberof trials

Median samplesize (number ofpatients enrolled)

Percentage oftrials using responserate as primary endpoint

Percentage of trials thatwere randomized

�1 20 73 75 30�2 48 74 85 23�3 54 78 80 26�4 68 74 79 25�5 71 74 79 25�6 99 94 73 33






AcknowledgmentsThe authors thank Jeff Fritsch of the Office of Orphan Product Devel-

opment (OOPD), FDA; Drs. Anthony Murgo, Robert Justice, and PatrickKeegan of the OHOP, CDER; Dr. Somesh Chattopadhyay of the Office ofBiostatistics, CDER, for their helpful discussions; Scott Freeman andDr. Kui Xu of OOPD, Dr. Anthony Murgo of OHOP and Kristiana Bruggerand Nancy Hayes of the Office of Regulatory Policy (ORP), CDER, fortheir critical reading of the manuscript; and regulatory project managersand medical officers in OHOP who helped to provide information used in

this article. Special thanks to Dr. Harry Smith of Office of Communica-tions, CDER, for his critical reading and editing of the manuscript andDr. Tamy Kim, Dianne Spillman, Susan Lange, and Christine Lincoln ofOHOP for their help in verification of information presented in Supple-mentary Table S1.

Received April 5, 2012; revised May 29, 2012; accepted June 6, 2012;published OnlineFirst June 20, 2012.

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2012;18:5172-5178. Published OnlineFirst June 20, 2012.Clin Cancer Res Himabindu Gaddipati, Ke Liu, Anne Pariser, et al. Rare Cancer Trial Design: Lessons from FDA Approvals

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