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Home , Chlorotrianisene, Cyclophosphamide, Plicamycin

11 1; -- __...._-----. ^.-- ______-..._._ _.__ - _...... - t Ji Jo United States General Accounting Office Washington, D.C. 20648

Program Evaluation and Methodology Division

B-242851

February 25,199l

The Honorable Edward M. Kennedy Chairman, Committee on Labor and Human Resources United States Senate

Dear Mr. Chairman:

In September 1989, you asked us to conduct a study on reimbursement denials by health insurers for off-label drug use. As you know, the Food and Drug Administration designates the specific clinical indications for which a drug has been proven effective on a label insert for each approved drug, “Off-label” drug use occurs when physicians prescribe a drug for clinical indications other than those listed on the label.

In response to your request, we surveyed a nationally representative sample of oncologists to determine:

. the prevalence of off-label use of anticancer drugs by oncologists and how use varies by clinical, demographic, and geographic factors; l the extent to which third-party payers (for example, Medicare intermediaries, private health insurers) are denying payment for such use; and l whether the policies of third-party payers are influencing the treatment of patients.

We randomly selected 1,470 members of the American Society of Clinical Oncologists and sent them our survey in March 1990. The sam- pling was structured to ensure that our results would be generalizable both to the nation and to the 11 states with the largest number of oncologists. Our response rate was 56 percent, and a comparison of respondents to nonrespondents shows no noteworthy differences between the two groups.

We have briefed your staff on the results of our survey. Subsequently, it was agreed that the data from our survey should be made publicly available as quickly as possible so that they can be used in policy formu- lation efforts at the Department of Health and Human Services and at private health insurance firms. Toward that end, we have reprinted our survey instrument and provided the responses in summary form (see appendix I). We are currently completing our analysis of the responses and expect to forward a fully detailed report to you shortly.

Page 1 GAO/PEMDBl-12BR Initial Off-Label Survey Results B-242651

We are sending copies of the survey responses to officials at the Food and Drug Administration, the Health Care Financing Administration, and the National Cancer Institute. We also will make copies available to pharmaceutical manufacturers, health insurers, and other interested parties upon their request.

If you have any questions or would like additional information, please call me at (202) 276-1854 or Robert L. York, Acting Director for Pro- gram Evaluation in Human Services Areas, at (202) 275-6885. Other major contributors to this report are listed in appendix II.

Sincerely yours,

Eleanor Chelimsky Assistant Comptroller General

Page 2 GAO/PEMDBl-12BR Initial Off-Label Survey Results Page 3 GAO/PEMD-91-12BR Initial Off-Label Survey Results Appendix I Survey Results

- On the pages that follow, we have reproduced the questionnaire mailed to a random sample of the membership of the American Society of Clinical Oncology in March 1990. For each response category, we pro- vide the number (or percent) of respondents that selected that response. The one exception is for questions from the patient-based portion of the questionnaire. The questionnaire requested information for three spe- cific patients being treated by the respondent and was structured so that questions 1 through 11 dealt with the first patient, questions 12 through 21 with the second, and questions 22 through 31 with the third. In presenting the responses, we have summed across all patients (for example, 55 percent of all patients were female, not 55 percent of the first patients described by physicians). Consequently, questions num- bered 12 through 31 do not appear in our report.

A total of 1,470 questionnaires were mailed and 680 responses were received. After adjusting for legitimate nonrespondents (for example, individuals who do not treat patients, who have retired, who do not use ), the response rate was 56 percent.

Page 4 GAO/PEMD-Ol-12BR Initial Off-Label Survey Results Appendix I Survey Results

United StatesGeneral Accounting ORlce Survey Of Off-Label Drug Use

The U.S. SenateCommittee on Labor and Human The questionnairebegins by askingyou to provide Resourceshas asked the GeneralAccounting Office informationabout the last three patients you saw,prior (GAO) to conducta study of the extentto which thereare to filling out this questionnaire,for whomyou prescribed reimbursementdenials when anticancerdrugs are used (or areabout to prescribe)an anticancerdrug therapy. for clinical indicationsother lhan that for which they GAO is only interestedin the patientsyou aretreating (or receivedapproval from the Foodand Drug aboutto treat) with anticancerdrugs and not the onesthat Administration. GAO is primarily interestedin you may haveseen to counselor rendera secondopinion. reimbursementproblems as they relateto off-label In order to answerthese patient-based questions, you anticancer drug use and the potentialeffects these may want to haveyour receptionistpull the chartson problemsmight haveon the therapiesgiven to cancer theselast threepatients. patients. Pleasereturn the completedquestionnaire in the enclosed This questionnaireis part of a nationalsurvey of preaddressedenvelope within two weeks. If morethan oncologistsand hematologistsin privatepractice. Its one doctor in a grouppractice receives a questionnaire, purposeis IOobtain informationfrom which to determine we requestthat eachdoctor respondseparately. the prevalenceof off-label anticancerdrug use;how off-label drug usevaries by patientcharacteristics, RESULTS: Responsesfrom all questionnaireswill be indication,and therapeuticintent; the extentto which aggregatedfor analysisand thereforeno responsewill reimbursementsare denied for off-label drug use;and the ever be associatedwith a particularpractice or individual. exlemto which reimbursementproblems have caused The final report will provideobjective information about doctorsIO alter the way they treat their cancerpatients. this issuefor congressionalreview and for the useof GAO is primarily interestedin the useof anticancerdrugs interestedparties. that areapproved for marketingrather than thosewhich areclassified as investigationalor ScheduleC drugs. Thank you for your timely response.If you haveany questionsabout the questionnaire,please call Tom Laetz INSTRUCTIONS: This questionnaireis divided into .at (303) 844-0082. threeparts and shouldbe completedby the doctor, with Ihe possibleassistance of an office or insurancemanager for Part III. The questionnaireshould take about 35 minutesto complete. Although it may appearlong, it is primarily composedof questionsthat ask you to check lhe drugsyou frequentlyuse in treatingdifferent typesof cancerfrom a commonlist of drugsprepared by GAO.

Page I5 GAO/PEMD-91-12BRInitial Off-Label Survey Results Appendix I Survey Resulta

PART 1: PATIENT CHARACTER~TICS AND PRESCRIBED TREATMENT-- ALL TRREE PATIENTS (Questions 1 to 31) The fusr part of the questionnaireSolicits responses 10qu*ltions aboutthe lnst three patients for which you prescribed shgle drug or combinationCytOlOXiC therapies.For eachpatient. you will be asked10 provide background information aboutthe patient.the diseasecharacteristics, and the anticancerdrugs prescribed for the patient’streatment regimen,

1. which of Ihe following prOfeSSiOn mostclosely 5. What is the primary site of the cancerin this patient? mabzhes your currentposition With this office? (Check one) (Check one) 2.1% Bladder 1 . 2% Hematologist 1.6 % Bone andconnective tissue 5 4 . 2 % Hematologist/Oncologist 2.3% Brain 5 . 9 % Gynecologicor urologic oncologist 21.0% Breast 2 9 -7 % Medicaloncologist 1.2% Cervix 4 .5 % Surgicaloncologist 13.9% Colorectal 4 . 5 % Other, please specify: 2.2% Headorneck 100.0% n=666 2.2% 2. In what agegroup does this patientbelong? (Check one) 0.4% 12.6% Lung 7 . 1% Under20 yearsold 1.3% Pancreas 26.5% 21 to50yearsold 2.6% FrOState 24.1% 51to6Oyearsold 6.9% @=y 27.5% 61to70yearsold 1.4% skin 13.4% 71 to80yeamold 1 .7 % Stomach 1.4% Over 80yearsold 100.0% n = 2014 1.3% Testis 3. What is the sex of this patient? 0.1% Thyroid 1.2% Uterus 55.3% Female 5 . 0 % Other,pleuse specify: ( 12 s i t es ) 44.7% Male 19 . 0 % Not applicable,i.e., hematologicmalignancies 100.0% n = 2019 4. Is the therapyfor this patientbeing provided as part 0.5% of a researchstudy? (Check one) 2.2% ALL 1.9% ANLL 22.8% y- 1.1% CLL 0.5% CML 77.2% No 0.5% 100.0% n = 2009 2.8% Hodgkins disease 6.9% Non-Hodgkins disease 2.6% Other n = 2018

Page 6 GAO/PEMD-Bl-12BRInitial Off-Label Survey Results Appemdix I Survey Results t

6. What is the stageof the cancerin this patient’?(Check 10. What othermodalities of treatmentare being one) consideredfor this patientduring the presentcourse of treatment? (Check all rhar apply) 0.3% lnsitu 2 5 .3 % Radiation 8.4% Localized 5 .4% Regionalby direct extensiononly 7.9% Surgery 5 8.2 % None otherconsidered 14.5 % Regionalto lymph nodesonly 8 .9 8 Other,please specify: 9 .6 % Regionalby direct extensionand to lymph n = 2040 nodes 4.2 % Regional.(NOS) 5 2 . 1% Distant metastasis 5 .5 % Unstaged.unknown or unspecified 100.0% n = 1943 7. What is the histologyof the cancer?

Hisr&gy: (omitted)

8. What modalitiesof treatmenthas this patienthad prior to the presentprescribed treatment regimen? (Check all that apply) 1 . R% Biological therapy 3 2 .3 % Chemotherapy 8 .8 % Hormonaltherapy 0 . 8 % 2 2.2 % Radiation 46.1% Surgery 2 5 .8 % No previoustreatment I) . 8 % olher, phase specify: n = 2040 9. What will be the primary therapeuticintent of the presentcourse of therapy?(Check one)

4 3 -8 %Curative 5 6 . 2 %Palliative 100.0% n = 2004

Page 7 GAO/PEMD-Bl-12BB Initial Off-Label Survey Beeults Appendix I Survey Results

11. Please check the anticancer drugs, including hormonal agents, that you prescribed for the patient’s present therapeuticregimen by modeof administration.

Betamethesone, Celestone Bteomycin, Blenoxane I 3 8) 41 . Myleran 10 0 1 . Velban I 2lll2~37l , Paraplaarin 0 49lcCl , BiCNU 3 18 23 , Leukeran 27 0 1 Cispiatin, Platinol 4 @3x% . Cytadren 4 0 0 , Cyroxan, Neosar 1% s m Chlorotrianisene, TACE 1 0 0 Cytarahine. Cyrosar-U 13fjHl Diethylstiibestrol. Srilphoswol 5 0 2 , DTIC-Dome 1 23 31 , Esrrace I 0 I 0 I 1 , Cosmegen 0 18 13 Fluoxvmesterone. Halotestin I 91 11 0 . Cerubidine Q 33 14 Flutamide, Eulexin I 20101 / 01, , Adriamycin 7 318 liTI Leucovorin, Folinic acid 45 56112 , Emcyr 3 0 1 Leuprolide acetate, Lupron 0123 0 , VePesid, VP-16 I 1511u212171 Medroxyprogesterone. Provera , FUDR 0 712 . Efudex, 5-FU 10 w, 265 Hydroxyurea. Hydrea 14 2 3 , IF&X 0 14 ti Octreotide acetate, Sandosrarin Interferon alfa 2aJb. Infron-A 093 4 Prod&tone 24422 4 , CeeNlJ. CCNU 11 1 2 , Nolvadex 121 3 4 Mechlorethamine, Mustargen, HN2 2 m 11 Testalactone, Teshc 0 0 0 Melphalsn, AIkeran 29 1 6 , Purinethol 23 3 5 INVESTIGATIONAL DRUGS 19xD 82 Interleukin, X2, IL2 wirh LAK II 4112 Mitomycin. Muramycin 05630 Levamisole 174 5 4 . Novanrrone 0 25 17 .Y Mirhracin 0 1 0 OTHER DRUGS:

Page 8 GAO/PEMD-Bl-12BR Initial Off-Label Survey Resulte Appendix I Survey Rem&a

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PART II: DRUG USE FOR SPECIFIC DISEASES

The secondpart of the questionnaireasks you to respondto questionsabout the anticancerdrugs that you usually prescribein treating 11 typesof cancer. For someof thesecancers you will be askedto identify the combinationof drugsthat you usually prescribein your first. second,and third lines of treatment.For other typesof canceryou will be askedto identify all the drugsthat you frequentlyuse. In eachcase you will be askedto check the drugsyou usefrom a commonlist of anticancerand hotmortaldrugs. We recognize,however, that your selectionof drugsfor eachpatient may vary for a numberof reasons.The remainingsection of this part thenasks you to indicateif the drugsthat you usually prescribefor thesecancers differ from the drugsyou would like to useand the reasonsfor any differences. Finally, we ask you to identify the sourcesyou rely on for drug information.

32. Which of the following professionsmost closely 33. ln your personalpractice, about what percentageof matchesyour cunent position with this office? your currentpatients are enrolled in clinical trials (Check one) from any source? (Check one) 1 .4% Hematologist 9.2 % No patientson 5 5 . 3 % Hematologist/Oncologist 53.5% 01t010percen1 5 . 7 %Ciynecologic or urologic oncologist 19.2% 11 to3Opercent 28 -8 % Medical oncologist 17.6% Over30perccnt 4 . 3 % Surgicaloncologist .5 % Unknownpercentage 100.0% n = 578 4 . 5 % Other,please sprcib: 100.0% n = 667

Page 9 GAO/PEMD-Sl-12BRInitial Off-Label Survey Resulta Appendix I Survey IZeauIta

34. What anticancerdrug combinationsdo you usually prescribe in treating acute non-lymphocytic leukernla? Please checkthe combinationof drugsused in your typical first, second,and third lines of treatment.

Drug Names Drug Names , Elspar . Matulane Bctamethasone, Celestone Thioguanine Bleomyctn, Btmoxane Thiotepa Busulfan, Myleran Vinblastine, Velbun Carboplatin. Paruplarin , Oncovin Carmustine, BiCNCJ Chlorambucil. Leukerun HORMONAL OR OTHER DRUGS , P/atino/ Aminoglutethimide. Cytadren Cyclophosphamide. Cyroxan, Neosar Chlorotrianisene, TACE , Cyrosar-U Diethglstilbestrol, Stilphostrol Dacarbazine, DTIC-Dome Estradiol, Estrace Dactinomycin , Cosmegen , Halotestin Daunorubicin, Cerubidine Flutamide. Eufexin Doxorubicin, Adriamycin Leucovorin, Folinic acid Estramustine, Emcyr Leuprolide acetate, Lupron Etoposide, VePesid, VP-16 Medroxyprogesterone. Provera Floxuridine, FtJDR , Megace 0 0 0 Fluorouracil, Efudex, 5-FU . Oreton -l-0 00H Hydroxyurea, Hydrea , Lysodren 0 0 0 Uosfamide, IFEX Octreotide acetate, Sandosratin Iktl0 00 Interferon alfa 2a$b, Inrron-A Prednisone 39 20 10 Lomustine, CeeNU, CCNU Tamoxifen, Nolvadex 0 0 0 Mechlorethsmine. Mustargen, HN2 Testalactone, Tesfac 0 0 0 , Alkeran Mercaptopurine. Purinerhol INVESTIGATIONAL DRUGS ti Methotrexate Interleukin, IL2, IL2 with LAK 0 0 0 Mitomycin. Muromycin Levamisole 0 0 0 Mitoxontrone. Novuntrone Plicamycin. Mithracin OTHER DRUGS: (8) Bm o 5 447 2025

Page 10 GAO/PEMDBl-12BR MtiaI Off-Label Survey Results Appendix I Survey Reaulta

-.--.- 35. What micaucer drugs, including hormonalagents, do you frequentlyuse iu treatingbreast cancer in 1 prcmenopausal women with adjuvaut therapy? Please checkh the drugsused. - .f Drug Names Drug Names &.f+ Asparaginase, E/spar Procarbazine. Marulane 00 Betametbasone, Cefestone Tbioguanine Bleomgcin, BIenoxane Thiotepa Busulfan, Myleran I 01 Vinblastine, Velban Carboplatin, Paraplatin 0 Vincristine, Oncovin Carmuatine, BiC/VU 2 Chlorambucil, Leukeran 0 HORMONAL OR OTHER DRUGS Cisplatin. Plafinol 11 Aminoglutethimide, Cyradren Cyclophosphamide, Cyroxan, Neosar 568 Chiorotrianisene, TACE Cytarobine, Cyrosar-U 0 , Srilphostrol Dacarbazine. DTIC-Dome 0 Estradiol, Esnace Dnctinomycin , Cosmegen 0 Fluoxymesterone, Haloresrin Daunorubicin. Cerubidine 9 Flutamide, Eulexin Doxorubicin, Adriamycin 457 Leucovorin, Folinic acid Estramustine. Emcyr 0 Leuprolide acetate, Lupron Etoposide, VePesid, VP-16 7 Medroxyprogesterone, Provera Floxuridine, FUDR 1 17 Megestrol acetate, Megace Fluorouracil, Efwlex, 5-FU I 550 Methyltestosterone, Oreron Hydroxgurea, Hydrea 0 Mitotane, Lysodren Ifosfamide. IFEX 0 Octreotide acetate, Sandosrarin Interferon alla 2a,2b, Inwon-A 0 Prednisone Lomustine. CeeNU. CCNU n Tamoxifen, Nolvadex Mechlorethamine. Musrargen, HN2 1 0 1 Testalactone, Teslac Melphalan, Alkeran 14 Mercaptopurine, Purinerhol 3 INVESTIGATIONAL DRUGS Methotrexate Interleukin, IL2, IL2 with LAK Mitomycin, Muramycin Levamisole Mitoxantrone. Novantrone 45 Plicamycin, Mirhracin 1 OTHER DRUGS: (4) 81 n = 573

Page 11 GAO/PEMDSl-1ZBR Initial Off-Label Survey Results Appendix I Survey Resuka

36. What anticancerdrugs, including hormonalagents, do you frequentlyuse in treatingbreast cancer in postmenopausal women with adjuvanttherapy? Please check all the drugsused. 1

Drug Names Procarbazine, Matulane Betamethasone, Celesrone Thioguanine 1 Bleomvcin. Blenuxone Thiotepa --i 14 Busulfan. Myleran I 01 Vinblastine, Velban 25 Carboplatin, Paraplarin 0 Vincristlne, Oncovin ---I86 Cannustine. BiCNU 1 Chlorambucil. Lrukeran 5 HORMONAL OR OTHER DRUGS Ctsplatin. Platinnl 5 Aminoglutethimide, Cyradren Cyclophosphamide, Cyroxan, Neosar 510 Chlorotrianisene. TACE Cytorabine, Cyrosar-U 1 Diethylstilbestrol. Srilphosnol Estradiol, Esrrace Fluoxymesterone, Halorestin Flutamide, Eulexin 1 Leucovorin, Folinic acid 20 Leuprolide acetate, Lupron 1 Etoposide, VePesid, VP-16 3 Medroxyprogesterone. Provera 11 Floxuridine, FUDR 17 Megestrol acetate, Megace 120 Fluorouracil, Efidex, 5-FU 493 Methyltestosterone, Oreron 2 Hydroxyurea, Hydrea 0 Mitotane. Lysodren 2 Ifosfamide. IFEX 0 Octreotide acetate, Sandosrarin 2 Interferon alla 2a,2b, Infron-A n Prednisone 107 I Lomustine. CeeNCJ,CCNll 0 Tamoxifen, Nolvadex 560 -1 Mechlorethamine, Musrargen, HN2 n Testalactone. Tesfac 1 Melphaian. Alkeran 9 =I Mercaptopurine, Purinerhol 0 INVESTIGATIONAL DRUGS Interleukln, IL2, IL2 wirh LAK 0 Levamisole 0

OTHER DRUGS: (2) 4 Pllcamycin, Mirhracin I 0 I 3 I n = 570

Page 12 GAO/PEMDSl-12BR Initial Off-Label Survey Results Appendix I Survey Rem&e

37. What anticancerdrug combination&including hormonal agents and disregardingmenopausal or estrogenreceptor status, do you usually prescribe in treating metastatic ? Pleasecheck the combinationof drugsused in your typical f’iist, second,and third lines of treatment.

& $4 Drug Names Asparaginase, E&w Procorbazine, Marulane m00 I I 0-, Betamethasone, Celesrone OIlI 01 Thioguanine IO 0 0 , BIenoxane Oil! 71 Thiotepa I 10 68 64 Busulhn, Myleran 00 a Vinblastine, Velban 10 lt34 226 Carboplatin, Parapfarin IHI0 7 24 Vincristine. Oncovin 6310% 40 Carmustine. BiCNU Chlorambucil, Leukeran HORMONAL OR OTHER DRUGS ‘:, ,i ‘: Cisplatin, Plarinof 4 25 97 Aminoglutethimide. Cyradren 4 48195 Cyclophosphamide. Cytoxan, Neosar +--I-494131 23 Chlorotrianisene, TACE 0 0 0 Cytarabine, Cytosar-V 01 1 Diethglstilbestrol, Srilphosf~ol i 6112131 Dacarbazine, DTIC-Dome 01 2 E&radio& Esnace 1 11 21 6 Dnctinomycin , Cosmegen 00 3 Fluoxymesterone, Halorestin Daunorubicin. Cerubidine #11 8 3 Flutamide, Eulexin Doxorubicin. Adriamycin 264257 41 Leucovorin, Folinic acid Estramustine. Emcyr 01 1 Eioposide. VePesid, VP-16 322 68 Floxuridine, FUDR --11 6H 6 --l Fluorouracil. Efudex, S-FU Methyltestosterone, Oreron 1 1 0 Hydroxyuren, Hydrea Mitotane. Lysodren 0 0 4, Ifosfamide. lFEX Octreotide acetate, Sandostatin I 01 01 21 Interferon alfa Za,2b, Innon-A Lomustine. CeeNU, CCNU Mechlorethnmine, Musrargen. HN2 Melphalnn, Alkeran Mercaptopurine, Purinerhol INVESTIGATIONAL DRUGS Methotrexate Interleukin, IL2, IL2 with LAK 01212 Mitomycin. Muramycin 2 3323 Levamisole Mitoxsntrone, Novannone ---l-24 76 63 H Plicnmycin. Milhracin 012 131 OTHER DRUGS: (4) ~ t 2 5 1 9 n = 560

Page 13 GAO/PEMD-91-12BR Initial Ofi’-L&e1 Survey Results Appendix I Survey Results

38. What anticancer drugs do you frequently use in treatingDukes ’ C colon cancer with ? Ph~e check all the drugs used.

Drug Names ’ Asparaginase, Elspar Betamethasone. Celesrone Thioguanine I 01 Bleomycin, Blenoxane 0 Thiotepa Busulfan. Myleran -40 Vinblastine, Velban Carboplatin. Paraplatin Carmustine. BiCNV Chlorambucil, Leukeran Cisplatin, Plarinol Cyclophosphnmide, Cyroxan, Neosar Cytarabine, Cyrosar-V Diethylstilbestrol, Sdlphostrol 0 Dacarbazine, DTIC-Dome Estradiol, Esrrace 0 Dactlnomycin , Cosmegen Fluoxpmesterone, Halorestin 0 Daunorubicin, Cerubidine Flutamide, Eulexin 0 Doxorubicin. Adriamycin Leucovorin, Folinic acid 336 Leuprolide acetate, Lupron 2 Etoposide, VePesid, VP-16 Medroxyprogesterone, Provera I 01 Floxuridine. FUDR Megestroi acetate, Megace I 01 Fluorouracil, Efudex, S-FU Methyltestosterone. Oreron Hydroxyurea, Hydrea 3 I Mitotane, Lysodren Uosfamide. IFEX 0 I Octreotide acetate, Sandosradn Interferon alfa 2a,2b, Inrron-A 10 Lomustine, CeeNV. CCNV ----I19 iI Mechlorethamine, Mustargen, HN2 0 I Testnlactone.Teslac 0 Melohalan. Alkeran 0 Mercaptopurine. Purinerhol 0 INVESTIGATIONAL DRUGS I Methotrexate 13 Interleukin. X.2. IL2 with LAK 1 Mitomycin. Muramycin 20 Mitoxantrone. Novanrrone 0 Plicamycin. Mirhracin 0 n = 548

Page 14 GAO/PEMD-91-12BRInitial Off-Label Survey Beeulta Appendix I Survey Remlta

39. What anticancer drugs do you frequently use in treating metastatic colon cancer? Please check all the drugs used.

Drug Names DWQ Names Asparaginase, E/spar Procarbazine, Matulane Betamcthasone. Celesrone Thioguanine Bleomycin, BIenoxane Thiotepa Busulfan, Myleron Vinblastine, Velban Carboplntin, Poruplurin Vlncristine. Oncovin Carmustine, BiCNU Chlorambucil, Lsukerun HORMONAL OR OTHER DRUGS Cisplatin. Platinol Aminoglutethimide, Cytudren Cyclophosphamide, Cyroxan, Neosar Chlorotrianisene, TACE Cytarabine. Cytosar-U 0 Diethylstilbestrol, Srilphosnol 0 Dacarbazine, DTIC-Dome Estradiol. Esrroce 3 j 0 Dactinomycin , Cosmegen 0 Fluoxymesterone, Halotestin 0 Daunorubicin, Cerubidine 0 Flutamide, Eulexin A0 Doxorubicin, Adriamycin 13 Leucovorin, Folinic acid 455 Estramustinc. Emcyt 0 Leuprolide acetate, Lupron 2 Etoposide, VePesid. VP-16 3 Medroxyprogesterone, Provera 0 Floxuridine. FUDR 3 Megestrol acetate, Megace 102 2 Fluorouracil, Efudex, 5-W 543 Methyltestosterone, Oreron 0 Hydroxyurea. Hydreo Mitotane, Lysodren 1 0 Ifosfamide, /FEX Octreotide acetate, Sundosrotin =I2 Interferon rlfa fa,2b, Intron-A Prednisone 3 Lomustine, CeeNU, CCNU Tamoxifen, Nolvadex A1 Mechlorethamine, Musrurgen, HN2 Testalactone, Tesluc 0 Melphaian, Afkerun ---I Mercaptopurine, Purinethol INVESTIGATIONAL DRUGS Methotrexatc Interleukin. IL.2, IL2 with LAK A14 Mitomycin, Mu~myrin Levamisole 35 Mitoxnnlrone, Nownrrnne Ill Plicamycin, Mirhrucin --I1 OTHER DRUGS: (4) -J12 n = 555

Page 15 GAO/PEMD-91-12BR Initial Off-Lab1 Survey Results Appendix I Survey Resulta

40. What anticancerdrug combinationsdo you usually prescribein treatingStage III B or IV A,B Hodgkin’s disease? Pleasecheck the combinationof drugsyou typically prescribefor your firs& second,and third lines of treatment.

I I I Thioguanine 1 11 01 0 Bleomycin, Blenoxune 1419]1791 16 Thiotepa I 01- 31- s- Busulfan. Uyleran 1~1 4 Vinblastine. Velban 411 189 !Tl5 Carboplatin. Parophrin 0 6 14 Vincristine, Oncovin 436162 25 Carmustine, BiCNU 18 61 33 Chlorambucil. Leukeran 41530 HORMONAL OR OTHER DRUGS Cisplotin, PIorinol 1 61 83 Aminoglutethimide, Cyrodren 0 0 0 Cyclophosphamide. Cytoxon, Neosor 446559 Chlorotrianisene, TACE 0 0 0 Cytarabine, Cyrosor-U 03544 Diethylstilbestrol, Stilphosnol I 01 01! 01 Dncarbazine, DTlC.Dnme ml50 10 Estradiol, Esnoce 0 0 0 Dactinomycin , Cosmegen 12 6 2 Fluoxymesterone, Halotestin 0 2 0 Daunorubicin, Cerubidine 7 7 1 Flutamide. Eulexin 0 0 0 Doxorubicin, Adriamycin 4B178 22 Leucovorin, Folinic acid 0 3 5 Leuprolide acetate, Lupron 0 0 0 Medroxyprogesterone, Provera 1 0 1 Megestroi acetate, Megace 0 0 0 Methyltestosterone, Oreron 0 0 0 Hydroxyurea. Hydrea I 01 01 21 Mitotane, Lysodren 0 0 0 Ifosfamide, IBEX 1185-z Octreotide acetate, Sondostutin 1 0 0 Interferon alla ZaJb, Intron-A 1 0 3 16 Prednisone 424 189 61 Tamoxifen, Nolvadex 0 0 0 31Mechlorethamine Musrargen HN2 Testalactone, Tesluc 0 0 0

Mercaptopurine, Purinethol 1 21 01 0 INVESTIGATIONAL DRUGS Methotrexate I II 25133 Interleukin, IL.2, IL2 wirh LAK 01 01 16 Mitomycin, Muromyrin 0 3 3 Levamisole Mitoxantrone. Novantrone 3n36 Plicamycin. Mirhracin 0 0 2 OTHERDRUGS: (5) BPfI = 18 [ Ij 181 p

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41. What anticancer drugs do you frequently use in treating hormone refractory cancer? Please check all the drugs used.

Bctamethasone, Celesrone 1 Thioguanine I 01 Bleomycin, Blenoxane 0 Busulfan, Myleran 0 Csrboplotin. Paraplatin 26 Carmustine, BiCNU I II Chlorambucil, Leukeran 3 HORMONAL OR OTHER DRUGS Cisplatin. Plarinol 151 Aminoglutethimide, Cyradren ---I61 Cyclophosphnmide. Cyroxan, Neosar 287 Chlorotrianisene, TACE 4 Cytarabine, Cytosar-U 1 Diethylstilbestrol. Srifphosnof -I31 Dacarbazine. DTIC-Dome I 01 Estradiol, Estrace I 41 Fluoxvmesterone. Halorestin I 01 Flutamide, Eulexin I 111 I Leucovorin, Folinic acid 32 Leuprolide acetate, Lupron 75 Medroxyprogesterone, Provera 3 Megestrol acetate, Megace 66 Fluorouracil, Efudex. S-FU 282 Methyltestosterone, Oreton 0 Iiydroxyurea, Hydrea 10 Mitotane, Lysodren 0 Ifosfamide, IFEX 12 Octreotide acetate, Sandosrarin 1 Interferon alfa Za,Zb, Innon-A 7 Prednisone 88 Lomustine. CeeNU, CCNU 0 Tamoxifen, Nolvadex 4 11 Mechlorethamine, Mustargen, HN2 0 Testalactone, Teslac 0 Melphalan, Alkeran I 71 Mercaptopurine, Purinethol 0 Methotrexate 80 Mitomycin, Muramycin 48 Levamisole Mitoxantrone, Novanrrone 15 Plicamycin. Mirhracin I 1 I OTHER DRUGS: (5) I 29 I n = 517

Page 17 GAO/PEMD-91-12BR Initial Off-Label Survey Results Appendix I Survey Results

42. What anticancerdrug combinationsdo you usually prescribein treatinglimited or extensivesmall cell lung cancer? Pleasecheck the combinationof drugsused in your typical first, second,and third lines of treatment.

Drug Names Drug Names Asparaginasc. E/spar I 01 01 0 Betamcthnsone. Celestone I 01 01 0 Bleomycin, Blenoxane 3 0 5 Buaulfan. Myleran 1 0 0 Carboplatin, Paraplarin 496553 Carmustine, BiCNU 2 11 31 Chlorambucil, Leukeran 1 0 0 HORMONAL OR OTHER DRUGS Cisolatin. Plarinol 1361lE8ll3 Aminoglutetbimide, Cytadren 01 II 0 Cyclophosphamide, Cytoxan. Neosar 1339(223( 56 Chlorotrianisene, TACE 0 0 0 Cytarabine, Cyrosar-U I 11I 01I 1 Diethylstilbestrol, Stilphosnol 0 0 0 Dacarbazine, DTIC-Dome 1 01 41 4 Estradiol, Estrace I 01I 01- 01- Fluoxymesterone, Halotestin 01 0 0 Flutamide, Eulexin 01 0 0 Leucovorin, Folinic acid 1 3 4 Leuprolide acetate,Lupron I 0 010 Etoposide, VePesid, VP-16 43 18) 47 Medroxyprogesterone. Provera 0 0 0 Floxuridine. FUDR 0 0 0 Megestrol acetate, Megace 1 0 1 Fluorouracil. Efudex. S-FU 2 4 17 Methyltestosterone. Oreton 0 0 0 Mitotane. Lysodren 0 0 0 Octreotide acetate, Sandosratin 0 0 0 ~: Prod&one 7 11 10 Tamoxifen, Nolvadex 0 0 0 Mechlorethamine. Mustargen, HN2 Testalactone, Teslac 0 0 0 Melohalan. Alkeran I 01 dl 11 Mercaptopurine. Purinethol I 01 01 II INVESTIGATIONAL DRUGS 1 I Methotrexate 14 61 133 Interleukin, U-2, IL2 with LAK 0 1 8 Mitomycin, Mutamycin .21 8 24 Levamisole 0 0 1 Mitoxantrone, Novantrone 1 9 11 Plicamycin. Mithracin 0 0 0 OTHER DRUGS: (5) 1 5 14

n=!X3

Page 18 GAO/PEMD-Ol-12BRInitial Off-Label Survey Results A~pe* I Survey Reaults

43. What anticancerdrugs do you frequentlyuse in treating metastatic non-small cell lung cancer? Pleasecheck all tie drugs used.

Drug Names Asparaginase, Elspar Betamethasone. Celesrone Bleomycln, Blenoxane Busulfan. Myleran Carboplatin. Paraplarin Carmustine. BiCNU Chlorambucll, Leukeran HORMONAL OR OTHER DRUGS Clsplatin, Plarinol Aminoglutethimlde. Cyrudren 0 Cyclophosphamide. Cyroxan, Neosar Chlorotrlanisene. TACE 0 Cytarabine, Cyrosur-II Diethylstilbestrol, Srilphosnol 0 Dacarbazine. DTIC-Dome Estradiol, Esrrace 0 Dactinomycfn , Cosmegen 0 Daunorubicin. Cerubidine --I9 Doxorubicin. Adriamycin 199 Estramustine. Emcyr 1 Leuprolide acetate. Lupron 0 Etoposide. VePesid. VP-16 394 Medroxyprogesterone, Provera 2 Floxuridine. FVDR 4 Megestrol acetate, Megace ! 4 Fluorouracil. Efudex, 5-FU 128 Methyltestosterone, Oreron I OI Iiydroxyurea, Hydrea --I3 Mitotane, Lysodren I 0 I Ifosfamide. IFEX 53 I Octreotide acetate, Sandosrarin I 0 I Interferon alfa 2aJb, Innon-A 4 I Prod&one 26 Lomustine. CceNV, CCNU 381 Tamoxlfen, Nolvadex 0 Mechlorethamine. Musrarnen. HN2 1 I Testalactone, Teslac 0 Melphalan, Alkeran Mercaotoourine, Purinerhol INVESTIGATIONAL DRUGS Methotrexate Interleukin, IL2, IL2 wirh LAK Mitomvcin. Muramvcin Levamisole Mitoxnntrone, Novanrrone Plicamycin. Mirhracin OTHER DRUGS: (3) 1 17

II = 530

Page 19 GAO/PBMDBl-12BR Initial Off-Label Survey Resulta Appendix I Survey Results

44. What anticancer drugs do you frequently use in treating metastatlc melanoma? Please check all the drugs used.

Thiotepa 4 Vinblastine. Velban 94 Carboplatln, Paraplarin 32 Vincristine, Oncovin 74 Carmustine, BiCNV l&J Chlorambucil, Leukeran 2 HORMONAL OR OTHER DRUGS 1 Cisplotin, Plurinol 279 Andnoglutethimide, Cyradren I 2 Cyclophosphamlde. Cyroxan, Neosar Chlorotrianisene, TACE I 1 Cytarobinc, Cyrosar-V I 1 Diethylstilbestrol, Srilphosrrol 1 Dacarbatine. DTIC-Dome I446 Estradiol, Estrace 0 Dactinomycin , Cosmegen I 34 Fluoxymesterone, Halorestin 1 0 Daunorubicin, Cerubidine 3 Flutamide, Eulexin ! 1 Doxorubicin. Adriamycin ti Leucovorin, Folinic acid Estramustine, Em@ 0 Leuprolide acetate, Lupron Etoposide, VePesid, VP-I 6 22 Medroxyprogesterone. Provera 1 4 Floxuridine. FVDR 0 Mepestrol acetate, Megace I 7 Fluorouracil, Efudex, 5-FU 11 Methyltestosterone, Oreron 0 Hydroxyureo, Hydrea 29 Mitotane. Lysodren 0 Lfosfamide, IFEX I 6 Octreotide acetate, Sundosrufin 0 Interferon alfa ZaSb, Inrron-A 1 lm Prednisone 12 Lomustine. CeeMV, CCNU I 82 Tamoxifen, Nolvadex 153 Mechlorethamine, Musrargen, HN2 2 Testalactone, Teslac 0 Melphalan. Alkeran l2 I Mercaptopurine, Purinerhol 0 INVRSTIGATIONAL DRUGS i Methotrexate 8 Interleukin. IL.2, IL2 wirh LAK Mitomycin, Muramycin 1 Levamisole Mttoxantrone. Novanrrone 1 Plicamyctn, Mirhrucin 0 OTHER DRUGS: (8) Rir = 2 I 25 n = 533

Page 20 GAO/PJZMD-91.12BR Initial Off-Label Survey Results Appendix I Survey Reaulta

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45. We haveheard that sometimesdoctors face barriersto the optimal treatmentof certain typesof cancer. For any of the 11 types of cancerfor which you just provideddrug treatmentinformation, is therea differencebetween how you veal thesediseases and how you would like to treat them? Pleasecheck the specific reasonsfor any differences.

Typesof Cancer 1. Acute non-lymphocytic 87.4% leukemia 1.8% 0.6% 2.4% 3.3% 4.5% n = 491 2. Localized breastcancer in premenopausalwomen 88.5% 1.0% 1.0% 5.7% 3.4% 0.4% n = 525 3. Localized breast cancer in 87.4% 1.0x 1.1% 7.1% 3.0% 0.4% n = 523 postmenopausalwomen 4. Metastaticbreast cancer 73.3% 6.1% 2.3% 7.2% 8.2% 2.9% n = 512 5. Localizedor regionalcolon cancer 67.8% 10.4% 2.2% 7.2% 8.6% 3.8% n = 500 6. Metatasticcolon cancer 61.6% 10.4% 4.9% 7.5% 13.0% 2.6% n = 509

7. StageIII or IV Hodgkin’s 90.1% 2.2% 0.4% 2.8% 3.2% 1.3% n=534 disease

8. Hormonerefractory prostate 70.7% 6.9x 4.2% 9.2% 6.6% 2.4% n - 498 cancer

9. Small cell lung cancer 78.7% 6.5% 1.6% 3.4% 8.0% 1.8% IL = 507

10. Non-small cell lung cancer 73.7% 8.3% 3.2% 4.7% 7.5% 2.6% n = 507

11. Metastaticmelanoma 67.6% 10.6% 2.2% 6.4% 9.4% 3.8% n = 499

12.Other reasons,pleosespecify: 19.6%

Page 21 GAO/PEMB-9l-12BRInitial GfY-LabelSurvey Results Appendix I Survey Results

46. Otherthan your training as an oncologistor hematologist,to what extent,if a1all, do you rely on eachof the following resourcesto learnmore about chemotherapy agents ’?

Technical Resource 1. Physician’s Desk Reference x x % x x 60.5 31.6 5.5 1.6 0.8 n = EB 2. AmericanHospital Formulary 78.5 16.2 3.8 1.3 0.2 n = 629 Service’s Drug Information 3. AmericanMedical Association’s Drug Evaluations 81.6 15.2 2.3 0.8 0.1 n = 619 4. Drug companypublications

Page 22 GAO/PEMD-91-12BR Mthl Off-Label Survey Results Appendix I Survey ReauIta

PARTm: EXTENT OF REIMBUESEMENT PROBLEMS

Thelut partof thi6 que6tionnairecan be answeredwith the assistanceof an office or insurancemanager, In this part, wesolicit rerpon6es to question6regudhtg theeXteCt1 IOwhich this practiceha6 faced problems in obtainingadequate 01timely reimbursement from third patty payers.Spefifically. GAO is interestedin reimbursementdenials that occurredwhen approved anticancer &us;6 were prescribed for off-label indications.Responses IO these question6 are brsedon reimbursementproblem6 the dOctOr’individual8 practice has faced over the last 12months.

47. Whichof (hefollowing profesSiOMmO6t ClOEely 50. During the last 12months, how muchof an increase, m(chesyour currentposition With this Office? if any, basthis individualpractice experienced in the (Checkone) time it takesIO receive reimbursement from third party payers?(Check one) 1 . 0% Hematologist 9.7% Noincrease 5 6 . 2 % Hemato~ogistK)nco~ogi6l 19.7 8 Someincrease 6 . 1% Gynecologicor urologiconcologist 3 0.4 %Moderate increase 2 5 . 0 % Medicaloncologirt 19 .9 %Great increase 1 .6 % oncologynurse 9 -8 % Very greatincrease 1.3% Insurancemanager lo. 5 % No basisto judge 2 _6 % OMcemanager 100.0% n - 589 0.5 93 Secretaryor bookkeeper 51. In the la6112 months,has this individualpractice 0.0% Billing agencyrepresentative experiencedany drug-relatedrtimburstment 5 .7 % Other,please specifi: problem6from third partypayers for the following 100.0% I-I = 617 reasons?(Check all that apply) 68.Is whichstate is this practicelocated? 50.7% Outpatientdrug administration, e.g.. infusion 5 1 -7% Useof an anticancerdrug for off-label Slate: (see last oaae) indicaIions 44 - 1% Ust of an investigationalanticancer drug 49.To what extent, if at all. doesthis individualpractice nndit difticult to keepup wilh the reimbursement 9 .7 % Otherreasons, please specifi: policiesof third partypayers7 (Check one) n= 617 52. Of your cancerpatient6 who couldnormally receive 15 . 2 % Little or no extent outpatienttreatment. approximately how many,if 18 .9 % Someextent any,ha6 Ibis individualpractice admitted to a hospitalin the last three monthsbecause a third 3 0 - 2 % Moderateextent party paytr would not reimbursefor the outpatient 2 2 . 2 % Greatextent administration(e.g.. by infusion)of anticancerdrugs? (Check one) 13 .7 % Verygreat extent 100.0% ” = 599 37.9% None 35.5% 1 IoSpatients 13 _6 a 6 to 10 p&at6 5.5 % 11 to 15 patients 2 -6 % 116IO 20 patients 4.9 % More than20 patients 100.0% n = 586

Page 23 GAO/PEMD-91-12BRInitial Off-Label Survey Results

I Appendix I Survey Results

53. Have oncologists and hematologists in this state 57. In the last 12 months, which of the following third reached any formal agreements with third party party payers have caused this individual practice lo payers, suchas Medicare intermediaries, regarding alter the way it would like lo lreat cancer patients? reimbursement for off-label anticancer drug use? By (Check all rhar apply) off-label we mean that an approved anticancer drug was prescribed for indications other than those 57 CHAMPUS suggested on tie package insert. (Check one) 15 8 Health Maintenance Organization 7.2% Yes 2 15 Medicare inretmediaries 43.1% No 7 g Preferred Physicians Organization 49. 7% No basis IO judge 146 Private third party insurer 100.0% n = 610 143 Public insurer, e.g., Medicaid 54. If this practice has had reimbursement problems in 3 3 Self administered employer insurer the last 12 months, have any reimbursement denials been due to the use of an anticancer drug for an 16 Other, please specify: off-label indication? (Check one) 58. Please list by name up to three third party insurers or 47.8% Yes--GOTOTHENBXTQUESTION managed care plans that have caused this individual 33.7% No --STOP,GOTOTHBLASTPAGE practice the most “hassle” regarding reimbursement for off-label anticancer drug use. 18.5 % No basis IO judge -- STOP, GO TO THE LAST PAGE 1. Medicare (36.6%), Blue Cross (19.7%) 100.0% n = 600 n= 238 55. During the last 12 months. has this individual Blue Cross (25.8%), Medicare (17.2%) practice experienced any increase in reimbursement 2. n= 186 denials for off-label anticancer drug use? (Check one) Medicare (19.2%), Blue Cross (15.4%) 2 0 . 1% Liltle or no increase 3. n= 104 3 a. 4 % Some increase 2 2 .8 % Moderate increase 9.4% Great increase 5 . 5 % Very great increase 3.8% No basis to judge 100.0% n = 289 56. In the lasf 12 months, has this individual practice been confromed by a new patient, arriving from another state, who seeks ueament with an approved anticancer drug (previously reimbursable) for which mird party payers in your stare are not willing IO provide adequate or timely reimbursement? {Check one) 15.4% yes 63.1% ~~ 2 1 . 5% No basis to judge lOO.g% n = 293

Page 24 GAO/PEMDBl-12BR Initial Off-Label Survey Results Appendix I Survey Results

59. If possible, please identify the anticancerdrugs that wereprescribed for off-label indicationsfor which reimbursementwas deniedduring the last 12 months. Pleaseidentify thesedrugs by indicatingthe primary site of Ihe cancerfor which they wereprescribed.

I Drug Names Primary Site Drug Names I Primary Site Asparaginase, Elspar 1 (1) Procarbazint, Matulane I l(l) Betamtthasont, Celesrone 0 (0) Tbioguanint 1 0 (0) Bltomycln. Blenoxane 4 (4) Thiotepa 1 6 (4) Busulfan, Myleran 1 (1) Vinblastine, Velban 9 (5) Carboplstin. Paraplarin 105 (17) Vincristine, Oncovin 5 (5) Carmustint, BiCNU 10 ( 4) Chlorambucil, Leukeran HORMONAL OR OTHER DRUGS 1 0 (0) ~- I Cisplatin, P/urinal 35 (12) Aminoglutethimide, Cyradren I 2 (-1) 1 Cyclophosphsmide, Cyroxan, Neosar 12 ( 5) Chlorotrianistne, TACE 0 (0) Cytarabine. Cyrosar-U 5 (4) Diethylstilbestrol, Srilphosnol 0 (0) Dacarbazint, DTIC-Dome 2 (2) Estradiol, &trace 0 (0) Dactinomycin , Cosmegen 1 (1) Fluoxymesterone, Haloresrin l(1) Daunorubicin, Cerubidine 1 (1) Flutamide. Eulexin 13 ( 2) Daxorubicin. Adriamycin 9 (5) Leucovorin, Folinic acid 85 (11) Estramustine, Emcyr 0 (0) Leuprolide acetate, Lupron 26 (6) Etoposidt, VePesid, VP-16 42 (11) Medroxyprogesterone, Provera 2 (2) Floxuridine. FUDR 12 ( 4) Megestrol acetate, Megace 12 ( 5) Fluorouracil. Efudex, S-FU 19 ( 8) Methyltestosterone, Oreron l(1) Hydroxyurea, Hydrea 2 (2) Mitotane, Lysodren 0 (0) Ifosfamide, IFEX 58 (15) Octrtotide acetate, Sandosratin 5 (3) Interferon alfa Za,Zb. Inrron-A 169 (14) Prednisone I l(1) I Lomustine, CeeNU, CCNU 9 (8) Tamoxifen, Nokadex I4(3’)1 Mtchlorethamine, Musrargen, HN2 0 CO)- Testalactone,Teslac Melphalan. Alkeran Mercaptopurine, Purinerhol OTHER DRUGS: 1 32 (14) 1

Note : The first number is the number of oncologists that responded to the question. The second number ( ) is the number of sites reported.

Page 26 GAO/PEMD-91-12BR Initial Off-Label Survey Results Appendix I Survey Resulta

60. If you haveany comments to makeabout this questionnaireor reimbursementproblems pertaining to the off-label useof anticancerdrugs, please express your thoughtsin the spaceprovided. Thank you.

Response8 to question 48

AK AL : AR 2 AZ 9 CA* 47 co 4 CT 11 DC 5 DE 4 FL* 44 GA 7 HI 0 IA 3 IL* 60 IN 7 KS 8 PY 12 LA 3 MA* 28 MD 25 HE 3 MI* 38 MN 15 MO 13 MS NC* 4: ND 3 NE 2 NH 0 NJ* 33 NM 5 NV 1 NY+ otl* z: 4 :"B 5 PA* 59 SC 2 TN TX+ 3: VA 11 WA WI :

n = 681

l States for which generalizations can be made from the data.

L

Page20 GAO/PEMD-91.12BRMtidOff-Labe1SurveyReeult.s Appendix II : Major Contributorsto This Report

Program Evaluation George Silberman, Assistant Director and Methodology Division, Washington, D.C.

Thomas J. Laetz, Project Manager Denver Regional Paul Gvoth, Technical Assistant Office Joseph Sikich, Staff Member

(978302) Page 27 GAO/PEMD-91-12BR Initial Off-Label Survey Results