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`Journal of Clinical Oncology
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`E n d P o i n t s a n d U n i t e d S t a t e s F o o d a n d D r u g A d m i n i s t r a t i o n
`A p p r o v a l o f O n c o l o g y D r u g s
`
`By John R. Johnson, Grant Williams, and Richard Pazdur
`
`Purpose: To summarize the end points used by the
`United States Food and Drug Administration (FDA) to ap-
`prove new cancer drug applications over the last 13 years.
`Materials and Methods: The FDA granted marketing ap-
`proval to 71 oncology drug applications between January
`1, 1990, and November 1, 2002. The end points used as the
`approval basis for each application are presented, and the
`rationale for each end point is discussed.
`Results: The FDA grants either regular marketing ap-
`proval or accelerated marketing approval for oncology
`drug applications. Regular approval is based on end points
`that demonstrate that the drug provides a longer life, a
`better life, or a favorable effect on an established surrogate
`for a longer life or a better life. Accelerated approval (AA) is
`based on a surrogate end point that is less well established
`
`THERE IS a common misperception that the United States
`
`Food and Drug Administration (FDA) requires a survival
`improvement for approval of oncology drug marketing applica-
`tions.1 This article reviews the marketing applications for oncol-
`ogy drugs approved by the FDA’s Division of Oncology Drug
`Products in the Center for Drug Evaluation and Research
`(CDER) from January 1, 1990, to November 1, 2002. The end
`points used as the approval basis for each application are
`presented, and the rationale for end-point selection is discussed.
`Regular marketing approval of oncology drugs requires sub-
`stantial evidence of efficacy from adequate and well-controlled
`investigations. The attributes of adequate and well-controlled
`investigations are described in the regulations.2 Studies must
`allow a valid comparison to a control and must provide a
`quantitative assessment of the drug’s effect. Guidance promul-
`gated in the 1980s indicated that efficacy should be demonstrated
`by prolongation of life, a better life, or an established surrogate
`for at least one of these. Drugs must also be safe for their
`intended use. The safety requirement comes from the Federal
`Food Drug and Cosmetic Act of 1938. A 1962 amendment to
`that Act codifies the efficacy requirement.
`
`From the Division of Oncology Drug Products (HFD-150), Center for
`Drug Evaluation and Research, United States Food and Drug Administra-
`tion, Rockville, MD.
`Submitted August 9, 2002; accepted December 23, 2002.
`The views expressed are the result of independent work and do not
`necessarily represent the views and findings of the United States Food and
`Drug Administration.
`Address reprint requests to John R. Johnson, MD, Food and Drug
`Administration, HFD-150, 5600 Fishers Lane, Rockville, MD 20857; email:
`Johnsonj@cder.fda.gov.
`© 2003 by American Society of Clinical Oncology.
`0732-183X/03/2107-1404/$20.00
`
`but that is reasonably likely to predict a longer or a better
`life. Tumor response was the approval basis in 26 of 57
`regular approvals, supported by relief of tumor-specific
`symptoms in nine of these 26 regular approvals. Relief of
`tumor-specific symptoms provided critical support for ap-
`proval in 13 of 57 regular approvals. Approval was based
`on tumor response in 12 of 14 AAs.
`Conclusion: End points other than survival were the ap-
`proval basis for 68% (39 of 57) of oncology drug marketing
`applications granted regular approval and for all 14 appli-
`cations granted accelerated approval from January 1,
`1990, to November 1, 2002.
`J Clin Oncol 21:1404-1411. © 2003 by American
`Society of Clinical Oncology.
`
`In 1992, Subpart H was added to the new drug application
`(NDA) regulations to allow accelerated approval (AA) for
`diseases that are serious or life-threatening when the new drug
`appears to provide benefit over available therapy, but under
`situations when the demonstrated benefit did not yet meet the
`standard for regular approval. For instance, AA can be granted
`on the basis of a surrogate end point that is reasonably likely to
`predict clinical benefit (Table 1) but that is not established to the
`level that would support regular approval. After AA, the appli-
`cant is required to perform a postmarketing study to demonstrate
`that treatment with the drug is indeed associated with clinical
`benefit. If the postmarketing study fails to demonstrate clinical
`benefit or if the applicant does not demonstrate due diligence in
`conducting the required study, the regulations describe a process
`for rapidly removing the drug from the market.3 The AA
`regulations provide drugs that are promising on the basis of
`surrogates that are reasonably likely to predict clinical benefit to
`patients with serious or life-threatening diseases. Drugs that are
`only similar to available therapy on the basis of such a surrogate
`would not appear to be especially promising and would not
`provide benefit over available therapy. If the drug showed
`clinical benefit, it would be granted regular approval and would
`not need to provide benefit over available therapy.
`In the early 1980s, the FDA approved oncology drugs based
`on tumor response rate alone. In the mid-1980s, on the advice of
`the Oncologic Drugs Advisory Committee (ODAC), the FDA
`determined that response rate generally should not be the sole
`basis for approval. The potential benefit associated with a partial
`response did not necessarily outweigh the substantial toxicity of
`oncology drugs, and the correlation between response rate and
`survival or clinical benefit was not well established. The new
`FDA position called for an improvement in survival or patient
`symptoms for regular approval.4
`In subsequent years,
`the FDA stated that under selected
`circumstances,
`impressive tumor-related outcomes could be
`
`1404
`
`Journal of Clinical Oncology, Vol 21, No 7 (April 1), 2003: pp 1404-1411
`DOI: 10.1200/JCO.2003.08.072
`
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`END POINTS AND THE FOOD AND DRUG ADMINISTRATION
`
`1405
`
`Table 1. Surrogate End Point Status and Marketing Approval
`
`End Point Status
`
`Established surrogate
`Reasonably likely surrogate
`Not reasonably likely surrogate
`
`Example
`
`Response rate in breast cancer with hormonal treatments
`Response rate in refractory solid tumors
`Tumor markers
`
`Type of Approval
`
`Regular approval
`Accelerated approval
`Not approvable
`
`the FDA and National
`considered clinical benefit. In 1991,
`Cancer Institute examined end points that potentially demon-
`strated clinical benefit. An improvement in disease-free survival
`(DFS) was proposed as a valid end point for an adjuvant
`setting if a large proportion of recurrences are symptomatic.
`Complete responses of reasonable duration may also represent
`evidence of clinical effectiveness. For example, complete
`responses in acute leukemia may correlate with improved
`survival and clinical benefits of
`reduced infections and
`transfusion requirements. Evaluation of response rates should
`take into consideration the response duration, the drug toxic-
`ity, and relief of tumor-related symptoms.5
`
`MATERIALS AND METHODS
`Information available to the public under the Freedom of Information Act
`was surveyed for new oncology drug applications and supplements for new
`uses approved by the Division of Oncology Drug Products from January 1,
`1990, to November 1, 2002. This survey does not include oncology drug
`applications approved by other CDER divisions, including drugs for skin
`cancer, hormone treatments for prostate cancer, or radiopharmaceuticals,
`and does not include biologic drug products, which are reviewed by the
`Center for Biologics Evaluation and Research. The primary source for
`this analysis was the package insert. When multiple end points were
`identified in the package insert and questions existed regarding the
`approval basis, other sources were consulted (medical officer review
`documents and ODAC meeting transcripts). The final arbiter in these
`cases was the approving official.
`End-point definitions were those used in the applications submitted to the
`FDA and can be found in approved labeling. The following general
`definitions were commonly used: complete response was complete disap-
`pearance of all tumor and all manifestations of tumor for at least 1 month;
`partial response was a 50% decrease from baseline in the sum of the
`cross-products of all bidimensionally measurable tumors lasting at least 1
`month; progression was a 25% increase in the sum of cross-products of all
`bidimensionally measurable lesions from the nadir value, the occurrence of
`new lesions, or obvious progression in evaluable disease. Disease-free
`survival was assessed from date of randomization until first recurrence or
`death. Survival was assessed from date of randomization to death. Skeletal-
`related events (SREs) formed a composite end point of pathologic fractures,
`radiation therapy, surgery to bone, or spinal cord compression. Statistical
`significance for time-to-event end points was determined by the log-rank test
`at a two-sided significance level of 0.05. Additional assessments of clinical
`benefit were descriptive or used end points described here.
`
`RESULTS
`
`End Points Used for Regular Approval
`Table 2 shows the end points that were the basis for the FDA
`marketing approval of oncology drug applications approved
`from January 1, 1990, to November 1, 2002. In addition to
`conventional anticancer drugs, this analysis includes approvals
`of four chemoprotectant and three bisphosphonate applications.
`Seventy-one marketing applications for oncology drugs were
`approved. Fifty-seven applications were granted regular ap-
`proval, and 14 applications were granted AA. Marketing ap-
`proval in 39 of the 57 applications granted regular approval was
`
`based on end points other than survival. Excluding chemopro-
`tectant and bisphosphonate applications, 34 of 52 regular ap-
`provals were based on nonsurvival end points. Table 3 tabulates
`the number of regular approvals using each end point.
`Survival.
`Survival was the primary approval basis for 18
`applications. This finding does not necessarily mean that only
`survival benefit could have led to approval
`in these cases.
`Whenever a survival benefit was demonstrated, it was designated
`as the primary approval basis.
`Tumor response, response duration, and time-to-tumor pro-
`gression.
`The FDA oncology drug approval record shown in
`Table 2 demonstrates that tumor response rate and time-to-
`progression were important end points in regular approval of
`oncology drugs. Forty-seven percent (27 of 57) of the regular
`oncology drug approvals had response rate or time-to-tumor
`progression (TTP) as the primary or coprimary end point in the
`trials supporting approval. Ten of these 27 approvals were based
`solely on tumor response, nine were based on both tumor
`response and relief of tumor-specific symptoms (see section on
`Relief of Tumor-Specific Symptoms or Improvement in Labo-
`ratory Findings), seven were based on both tumor response and
`TTP, and one was based on TTP alone.
`Regular approval of oncology drug applications based on
`tumor response or TTP indicates that these end points were
`considered surrogates for a better life and possibly improved
`survival in selected clinical settings. Considerations include
`efficacy of other available therapy, drug toxicity,
`type of
`response (complete or partial), response duration, and sup-
`portive data on disease-specific symptom improvement. A
`discussion of
`the rationale for
`these approvals follows.
`Further information can be found in the package inserts of the
`oncology drugs listed in Table 2.
`Anastrazole, exemestane, letrozole, toremifene, and fulves-
`trant were granted regular approval for treatment of advanced
`breast cancer in postmenopausal women on the basis of random-
`ized controlled trials (RCTs) comparing each with tamoxifen or
`another approved hormonal agent. Given the favorable toxicity
`profile associated with hormonal drugs compared with conven-
`tional cytotoxic agents, tamoxifen’s well-accepted therapeutic
`role, and the lack of a demonstrated survival effect with any
`hormonal drugs, response rate and TTP are considered adequate
`surrogates for a better life in hormonal drug trials in advanced
`metastatic breast cancer and have been the primary end points
`for comparing efficacy.6,7 At the time of approval in each case,
`a preliminary survival analysis was performed and showed no
`disadvantage compared with the control. Final survival data were
`assessed after approval.
`Tumor response was judged to represent clinical benefit in
`several other regular approvals. Durable complete responses are
`considered an established surrogate for a better life in refractory
`
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`1406
`
`Table 2.
`
`Drug (year, application type)
`Altretamine (1990, N)
`Altretinoin gel (1999, N)
`Amifostine
`(1995, N)
`
`(1996, S)
`
`(1999, S)
`
`Anastrozole
`(1995, N)
`(2000, S)
`(2002, S)
`
`Arsenic trioxide (2000, N)
`
`Bexarotene capsules
`(1999, N)
`Bexarotene gel (2000, N)
`
`Bleomycin (1996, S)
`Busulfan injection (1999, S)
`
`Capecitabine
`(1998, N)
`(2001, S)
`(2001, S)
`
`Carboplatin (1991, S)
`Carmustine wafer (1996, N)
`Cladribine (1993, N)
`Dexrazoxane (1995, N)
`
`Docetaxel
`(1996, N)
`(1996, S)
`(1999, S)
`Epirubicin (1999, N)
`Exemestane (1999, N)
`Fludarabine (1991, N)
`
`Fulvestrant (2002, N)
`Gemcitabine
`(1996, N)
`
`(1998, S)
`Gemtuzumab ozogamicin
`(2000, N)
`Idarubicin (1990, N)
`Imatinib mesylate
`(2001, N)
`
`(2002, S)
`Irinotecan
`(1996, N)
`(1998, S)
`(2000, S)
`Letrozole
`(1997, N)
`(2001, S)
`Leucovorin (1991, S)
`
`Liposomal cytarabine
`(1999, N)
`Liposomal daunorubicin
`(1996, N)
`Liposomal doxorubicin
`(1995, N)
`(1999, S)
`Methoxsalen (1999, N)
`
`JOHNSON, WILLIAMS, AND PAZDUR
`
`End Points for Approval of Oncology Drug Marketing Applications January 1, 1990 to November 1, 2002
`Approval
`Type
`Regular
`Regular
`
`End Points Supporting Approval
`
`RR
`RR, cosmesis
`
`Indication
`Refractory ovarian cancer
`Kaposi’s sarcoma, cutaneous lesions
`
`Trial Design
`SAT
`RCT
`
`To decrease cisplatin-induced renal toxicity in
`refractory ovarian cancer
`To decrease cisplatin-induced renal toxicity in
`lung cancer
`To decrease xerostomia after radiation
`therapy for head and neck cancer
`
`Regular
`
`AA
`
`Regular
`
`Creatinine clearance, CR and TTP to assess
`potential tumor protection
`Creatinine clearance, RR to assess tumor
`protection
`Salivary production and xerostomia scores RCT
`
`RCT
`
`SAT
`
`Regular
`Regular
`AA
`
`RR, TTP
`RR, TTP
`DFS
`
`Regular
`
`CR and CR duration
`
`RR, composite assessment of index lesion
`severity
`RR, composite assessment of index lesion
`severity
`Recurrence of effusion
`DFS, time to engraftment
`
`RR
`Survival
`Survival
`
`Regular
`
`Regular
`
`Regular
`Regular
`
`AA
`Regular
`Regular
`
`Regular
`Regular
`Regular
`AA
`
`AA
`Regular
`Regular
`Regular
`Regular
`Regular
`
`Regular
`
`Regular
`
`Regular
`AA
`
`Breast cancer, second-line treatment
`Breast cancer, first-line treatment
`Breast cancer, adjuvant therapy of
`postmenopausal patients with ER-positive
`tumors
`Acute promyelocytic leukemia, second-line
`treatment
`Cutaneous T-cell lymphoma, skin lesions
`
`Cutaneous T-cell lymphoma, skin lesions
`
`Malignant pleural effusions
`CML, conditioning regimen for stem-cell
`transplantation
`
`Breast cancer, refractory
`Colon cancer, first-line treatment
`Breast cancer, with docetaxel after failed
`anthracycline treatment
`Ovarian cancer, first-line treatment
`Recurrent glioblastoma multiforme
`Hairy cell leukemia
`To decrease doxorubicin-induced
`cardiotoxicity
`
`Breast cancer, second-line treatment
`Breast cancer, second-line treatment
`NSCLC, second-line treatment
`Breast cancer, adjuvant treatment
`Breast cancer, second-line treatment
`Refractory chronic lymphocytic leukemia
`
`Breast cancer, second-line treatment
`
`Pancreatic cancer
`
`NSCLC
`Acute myelogenous leukemia, second-line
`treatment in elderly patients
`Acute myelogenous leukemia
`
`CML, blast phase, accelerated phase, and
`failing interferon
`Gastrointestinal stromal tumors (GISTs)
`
`Colon cancer, second-line treatment
`Colon cancer, second-line treatment
`Colon cancer, first-line treatment
`
`Breast cancer, second-line treatment
`Breast cancer, first-line treatment
`In combination with FU for metastatic colon
`cancer
`Lymphomatous meningitis
`
`Kaposi’s sarcoma
`
`DB RCT
`DB RCT
`DB RCT
`
`SAT
`
`SAT
`
`SAT
`
`RCT
`RCT
`
`SAT
`RCT
`RCT
`
`RCT
`
`RCT
`SAT
`
`RCT
`
`SAT
`
`SAT
`
`SAT
`RCT
`RCT
`
`DB RCT
`DB RCT
`RCT
`
`RCT
`
`RCT
`
`SAT
`SAT
`SAT
`
`Pathologic CR, PFS, survival
`Survival
`CR and CR duration
`Cardiotoxicity (clinical and MUGA scans),
`RR to assess potential tumor protection
`
`RCT
`Placebo RCT
`SAT
`Placebo RCT
`
`RR
`RR, TTP, survival
`TTP and survival
`DFS and survival
`RR and TTP
`CR and PR, improvement in anemia and
`thrombocytopenia
`RR and TTP
`
`SAT
`RCT
`RCT
`RCT
`DB RCT
`SAT
`
`DB RCT
`
`Survival, clinical benefit response
`(composite end point including pain,
`performance status, and weight gain)
`RR, TTP, survival
`CR and CRp (CR with decreased platelets)
`
`Regular
`
`CR and survival
`
`AA
`
`AA
`
`AA
`Regular
`Regular
`
`Regular
`Regular
`Regular
`
`Hematologic response and cytogenetic
`response
`RR
`
`RR
`Survival
`Survival
`
`RR, TTP
`RR, TTP
`Survival
`
`AA
`
`Cytologic response
`
`Regular
`
`RR, TTP, cosmesis
`
`Kaposi’s sarcoma, second-line treatment
`Ovarian cancer, refractory
`Cutaneous T-cell lymphoma, skin lesions
`
`AA
`AA
`Regular
`
`RR
`RR
`RR based on overall skin scores,
`improvement in edema and scaling, and
`fissure resolution
`
`
`
`5 of 10
`
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`
`

`

`END POINTS AND THE FOOD AND DRUG ADMINISTRATION
`
`Table 2.
`
`Drug (year, application type)
`Mitoxantrone (1996, S)
`
`End Points for Approval of Oncology Drug Marketing Applications January 1, 1990 to November 1, 2002 (Continued)
`Approval
`Type
`Regular
`
`Indication
`Patients with pain from hormone-refractory
`advanced prostate cancer
`Colon cancer progressing after bolus 5 FU/
`LV and irinotecan
`
`Refractory ovarian cancer
`Breast cancer, second-line treatment
`
`Kaposi’s sarcoma
`
`Ovarian, first-line
`NSCLC
`Breast cancer, adjuvant therapy
`
`Skeletal morbidity of osteolytic bone
`metastases of myeloma
`Skeletal morbidity of osteolytic bone
`metastases of breast cancer
`
`End Points Supporting Approval
`Decrease in pain
`
`AA
`
`RR and TTP
`
`Regular
`Regular
`
`Regular
`
`Regular
`Regular
`Regular
`
`Regular
`
`Regular
`
`Durable PRs in bulky tumors
`TTP
`
`RR and clinical benefit (assessed by
`evaluating photographs)
`Survival
`TTP and survival
`DFS and survival
`
`SRE
`
`SRE
`
`Oxaliplatin (2002, N)
`
`Paclitaxel
`(1992, N)
`(1994, S)
`
`(1997, S)
`
`(1998, S)
`(1998, S)
`(1999, S)
`Pamidronate
`(1995, N)
`
`(1996, S)
`
`Pentostatin
`(1991, N)
`
`(1993, S)
`Porfimer sodium
`(1995, N)
`
`(1998, S)
`(1998, S)
`
`Talc (1997, N)
`
`Tamoxifen
`(1990, S)
`
`(1998, S)
`
`(2000, S)
`
`Temozolomide (1999, N)
`Teniposide (1992, N)
`
`Topotecan
`(1996, N)
`(1998, S)
`
`Toremifene (1997, N)
`Tretinoin (1995, N)
`
`Vinorelbine (1994, N)
`Zoledronic acid (2002, N)
`
`1407
`
`Trial Design
`RCT
`
`RCT
`
`SAT
`Dose-response
`RCT
`SAT
`
`RCT
`RCT
`RCT
`
`Placebo RCT
`
`Placebo RCT
`
`SAT
`
`RCT
`
`SAT
`
`SAT
`RCT
`
`RCT
`
`Placebo RCT
`
`Placebo RCT
`
`Placebo RCT
`
`SAT
`SAT
`
`RCT
`RCT
`
`RCT
`SAT
`
`RCT
`
`Hairy cell leukemia, second-line treatment
`
`Hairy cell leukemia, first-line treatment
`
`Regular
`
`Regular
`
`CR and CR duration, improvement in
`hemoglobin, WBC, platelets
`CR and CR duration
`
`For PDT in completely obstructed esophageal
`cancer
`For PDT of CIS and microinvasive NSCLC
`For PDT of completely or partially obstructing
`endobronchial NSCLC
`To prevent recurrence of malignant pleural
`effusion
`
`Node-negative breast cancer, adjuvant
`therapy
`To reduce the incidence of breast cancer in
`women at high risk
`To reduce the incidence of breast cancer after
`treatment of DCIS
`Anaplastic astrocytoma, refractory
`Refractory childhood acute lymphoplastic
`leukemia
`
`Regular
`
`Luminal response and palliative response
`
`Regular
`Regular
`
`Regular
`
`CR and CR duration
`Luminal response and pulmonary symptom
`severity scale
`Recurrence of effusion
`
`Regular
`
`DFS
`
`Regular
`
`Occurrence of breast cancer
`
`Regular
`
`Occurrence of breast cancer
`
`AA
`Regular
`
`RR
`CR and CR duration
`
`Ovarian cancer, second-line treatment
`Small cell lung cancer, second-line treatment
`
`Regular
`Regular
`
`RR, TTP, survival
`RR and response duration, symptom
`improvement
`RR, TTP
`CR
`
`Survival
`SRE
`
`Regular
`Regular
`
`Regular
`Regular
`
`Breast cancer, first-line treatment
`Acute promyelocytic leukemia, second-line
`treatment
`NSCLC
`Multiple myeloma and bone metastases from
`solid tumors
`Abbreviations: N, new drug application; RR, response rate; SAT, single-arm trial; RCT, randomized controlled trial; S, supplement; CR, complete response; TTP, time to
`progression; AA, accelerated approval; DB, double blind; ER, estrogen receptor; DFS, disease-free survival; CML, chronic myelogenous leukemia; PFS, progression-free
`survival; MUGA, multiple-gated acquisition; FU, fluorouracil; LV, leucovorin; PDT, photodynamic therapy; CIS, carcinoma-in-situ; NSCLC, non–small-cell lung cancer; DCIS,
`ductal carcinoma-in-situ; SRE, skeletal-related event.
`
`ovarian cancer. Altretamine was approved on the basis of a small
`number of durable complete responses in patients with refractory
`ovarian cancer. Before the AA regulations, paclitaxel was
`approved on the basis of durable partial responses in refractory
`ovarian cancer.
`Pentostatin, cladribine, tretinoin, and arsenic trioxide were
`granted regular approval for treatment of hematologic malig-
`nancies on the basis of durable complete responses, many
`lasting 6 months or longer. In these settings, durable complete
`responses were considered an established surrogate for a
`better life and possibly a longer life. Fludarabine was ap-
`proved for refractory chronic lymphocytic leukemia on dura-
`
`ble complete and partial responses associated with improve-
`ments in anemia and thrombocytopenia.
`Regular approval of topotecan in refractory small-cell lung
`cancer was based on both response rate and symptom benefit.
`The ODAC indicated that the topotecan tumor response (20%
`with median response duration of 14 weeks) was associated with
`decreased morbidity and mortality in this disease setting of rapid
`clinical progression and short survival.8
`A randomized controlled trial comparing two doses of
`paclitaxel and demonstrating an advantage in TTP with the
`higher dose was the approval basis for paclitaxel for second-
`line treatment of advanced metastatic breast cancer. Bleomy-
`
`
`
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`
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`

`1408
`
`Table 3. Summary of End Points for Regular
`Approval of Oncology Drug Marketing Applications
`January 1, 1990 to November 1, 2002
`
`Total
`Survival
`RR
`RR alone
`RR ⫹ decreased tumor-specific symptoms
`RR ⫹ TTP
`Decreased tumor-specific symptoms
`DFS
`TTP
`Recurrence of malignant pleural effusion
`Occurrence of breast cancer
`Decreased impairment of creatinine clearance
`Decreased xerostomia
`
`57
`18
`26
`10
`9
`7
`4
`2
`1
`2
`2
`1
`1
`
`Abbreviations: RR, response rate; TTP, time to progres-
`sion; DFS, disease-free survival.
`
`cin and talc were approved for treatment of malignant pleural
`effusions on the basis of time-to-recurrence of malignant
`pleural effusion, an end point closely related to TTP and
`symptom development.
`DFS. DFS may be the approval basis in the adjuvant setting
`if a high proportion of symptomatic recurrences is present or if
`a strong correlation with survival exists. A relatively long
`interval between recurrence and death also supports the use of
`DFS. DFS has supported approval of applications for adjuvant
`therapy for breast cancer and the use of busulfan in the transplant
`setting for chronic myelogenous leukemia. In the anastrozole
`application for adjuvant treatment of breast cancer in postmeno-
`pausal women, DFS supported AA rather than regular approval
`because the follow-up duration was insufficient for the latter type
`of approval.
`Time to treatment failure. No approvals were based on time
`to treatment failure (TTF). TTF is usually defined as the time
`from randomization to treatment discontinuation for any reason,
`including disease progression, treatment toxicity, patient prefer-
`ence, or death. TTF is a composite end point that is seldom
`useful for regulatory purposes. Discontinuance because of tox-
`icity, for example, has no direct relevance to effectiveness.
`Because the FDA must determine that approved drugs are both
`safe and effective, separate analyses of the efficacy and safety
`components of TTF (TTP, survival, and toxicity) are required for
`oncology drug marketing application approval.
`Relief of tumor-specific symptoms or improvement in labora-
`tory findings. Relief of tumor-specific symptoms alone was the
`basis for regular approval in four of 57 applications and provided
`support for regular approval in nine other applications. Mitox-
`antrone’s approval for treatment of hormone-refractory prostate
`cancer was based solely on pain relief. In a randomized con-
`trolled trial, the approval end point was a two-point decrease on
`a six-point pain scale lasting at least 6 weeks. Pamidronate and
`zoledronate were approved for prevention of morbidity from
`bone lesions of multiple myeloma and solid tumors on the basis
`of a composite symptom benefit end point described in the
`section on Composite Clinical Benefit End Points.
`Several applications for treatment of cutaneous manifestations
`of malignancy were approved on response rates augmented by
`
`JOHNSON, WILLIAMS, AND PAZDUR
`
`descriptions of clinical benefit in responding individual patients.
`Alitretinoin gel was approved for treatment of cutaneous Kapo-
`si’s sarcoma (KS) on the basis of cutaneous tumor responses.
`Cutaneous tumor responses were considered a clinical benefit
`because symptomatic skin lesions of the hands, feet, groin, and
`other areas responded with symptomatic relief. Cosmetic im-
`provement of disfiguring lesions was also considered evidence of
`clinical benefit. Paclitaxel was approved for second-line treat-
`ment of KS on the basis of response rate and retrospective
`collection of symptom relief information; for example, improved
`ambulation with KS involving the feet, healing of cutaneous
`ulcers, and resolution of disfiguring facial lesions.
`In first-line treatment of KS, liposomal daunorubicin was
`approved on the basis of a randomized controlled trial comparing
`it with standard combination chemotherapy using the end points
`of response rate, TTP, and photographic evidence of cosmesis
`and other clinical benefit. Liposomal doxorubicin received AA
`rather than full approval on the basis of tumor response rates that
`were no