EIR: Stanislaw R. MD, 8/6-10/01 Research Institute Joel Martinez 9432 Old Katy Rd'. Houston,TX. 77055 Summag of Findings Present directed inspection of this clinical investigator was conducted per request. dated June 7. 2001. from HFD-47. Good Clinical Practice Branch ll, Division of Scientific Investigations. CDER (FACTS #213702). The purpose of this inspection was to determine this clinical investigators compliance with applicable regulations. The inspection was conducted under CP7348.811. Clinical investigators. Inspectional coverage was given to study protocols under IND lb) (4) (Antineoplastons AS2-1 A10 injections) and IND (4) (Antineoplaston AS2- A10 capsules). Specific coverage was given to patients reported as complete responders (CR) and partial responders (PR) in the firm's annual report(s). Significant objectionable included but were not limited to the following: - Enrollment of subjects into antineoplaston study protocols prior to the protocol-specified interval following prior chemotherapy andlor radiation therapy. - Failure to report all serious adverse events (SAE's) and adverse events (ABS) to the agency and/or IRB. Failure to follow proper informed consent procedures. Failure to maintain adequate drug accountability records. - Discrepancies between the case report forms and source documents. At the conclusion of the inspection an FDA 483, Inspectional observations. was issued to and discussed with the clinical investigator. No samples were collected. Histogg of Business Research Institute (BRI). 9432 Old Katy Rd., Houston, TX. 77055 IS under the direction of Stanislaw R. M.D., Dr. is a holder of two EIR: Stanislaw R. MD.. 315-10101 1. IND (4) Anlineoplaston A10 and A82-'l intravenous injections. 2. IND (4) Antineoplaston A10 8. AS2-1 capsules. Dr. has phase II studies under IND (4) and approximately clinical studies under IND (4) In May 1984 a Permanent Injunction was ordered on the Cancer Research Institute and Dr. Refer to Exhibit 1 for a copy of the final judgment. In 1993 the National Institutes of Health (NIH) filed an IND but was withdrawn in July 1995. Reportedly. Dr. declined to supply antineoplastons. In February 1996 in response to FDA inquiries about patients being treated off protocol without the agency's knowledge and following a federal judge's order (that no patient may be treated outside a protocol). Dr. began to file the first of study protocols. Patients antineoplaston treatment were entered into a special protoco calls A -0 . In August 1997 Dr. annual reports noted in patients on the breast cancer study (Protocol BR-12) and (4) in patients on For non-small cell lung cancer (Protocols LA-3, LA-4, LA-5, and LA-6). Dr. annual report noted (4) in patients on protocol and patients entered under (4) Because of thesereported responses in these two groups of individuals, (4) for patients with breast and non-small cell lung cancer. Refer to Exhibit 2. Persons Interviewed and Individual Responsibility It should be noted that on 7-30-01, I called the BRI and asked to speak with Dr. to notify him of our intent to conduct a data audit inspection. His secretary stated that he was with a patient but that she would leave a message with him. I explained to her that we would like to begin the inspection Monday (8-6-01) on/about 9:00am. She said OK. On that same day (bl (7l(C) called to ask if we could postpone the audit until 8-20-01. I explained to her that because of travel arrangements that had already been made that would not be possible. She asked if that meant lsaid yes. On 7-31-01 I received a message from Barbara Tomaszewski, Business Manager_ for BRI. Her phone message stated that the person in charge of clinical trial documentation is out of the country and would not return until 8-20-01. I returned her telephone call and left two messages.- She then telephoned Dwight Herd. SCSO, SA-RP. Dwight Herd, SCSO and I then had a telephone EIR: Stanislaw R. M-D-. conversation with Ms. Tomaszewski. As a result of the telephone conversation and consultation with Dr. of DSI. we decided to fax a list (Exhibit 3) of those patients that had been reported as PR's (partial responders) and CR's (complete responders). The list was then faxed to BRI prior to the inspection. This was done to facilitate BRl's compilation of the patient tiles. source documents, and related study records and to facilitate the absence of this individual that was out of the country. On the first day of the inspection. the FDA inspection team consisted of myself. Patrick D. Stone. Investigator. and Khin Maung U. M.D.. Medical Officer, Good Clinical Practice Branch ll (HFD-47). Credentials were shown to and an FDA 482. Notice of inspection. was issued to Dr. Stanislaw R. Principal Investigator. Refer to Exhibit 4 for a list of individuals also present at the initiation of the inspection. Dr. is the principal investigator for all clinical studies and most responsible individual. His CV is attached as Exhibit 5. He provided organizational charts (Exhibit 6) for the following: 1. Organization of Medical Departments. 2. Organization of the Department of Medical Documentation and Clinical Trials Supervision. 3. Organization of the Department of Medical Data Processing Management, Statistics and Clinical Trials Dr. has three licensed physicians. They include: - Robert I. Lewy. M.D.- Refer to Exhibit 7 for his CV. 0 Marc Bestak. M.D.- See Exhibit 8 for his CV. Robert A. Weaver. M.D.- See Exhibit 9. All other M.D.'s listed in the organizational charts are not licensed. Their CV'siresumes are attached as Exhibit 10. Dr. stated that he currently has active protocols. He also mentioned that one protocol (CAN-D1) has been terminatedlclosed. I first asked Dr. for the source of his patients. He stated that the majority of prospective patients that present to the clinic_ do not qualify for entry into a study protocol, therefore, are treated with traditional FDA approved drugs/treatments i.e. radiation or chemotherapy. Dr. then added that approxirnatelymof his patients are treated withantineoplastons. He stated that prospective pa ients learn of his clinic by word of mouth or are referred by ELR: Stanislaw R. M.D.. 3/6-l0f0l other patients. Dr. stated that he currently has patients. Dr. stated that he does not advertise for patients to participate in his clinical trials. I asked Dr. to describe an individual's qualification into a clinical study. He stated that a selected patient is asked to provide medical records to include previous oncology reports. tissue slides. scans/films. and a description of previous treatments. Dr. stated that an "associate conducts the telephone interview and performs the initial review of the medical records. Dr. stated that he has approximatelyassociate M.D.'s on staff. These associate M.D's are listed in the organizational charts. If the patient appears to qualify after the initial review. the patient is asked to come to the BRI for a physical examination and further evaluation by 3 physicians that include a research physician, a senior physician. and Dr. Dr. stated that he makes the final decision with respect to one's participation in an antineoplaston clinical study. Dr. also stated that if a patient does not qualify or meet the criteria for a study protocol they may enter a clinical study through a special exemption from the FDA. He stated that a non-qualifier may also be referred to the (4) - I then asked Dr. to describe the informed consent process. He stated that an associate M.D. reads and explains the informed consent form to the patient and discusses the details of the clinical study. The patient is also asked to read the informed consent form. Dr. stated that after the informed consent form is fully understood by the patient and the individual has no other questions. he will then explain the possible adverse events with the patient. After the adverse events are understood the patient and Dr. Burzyinski sign the document. The patient is then started on the protocol. BRl's standard operating procedure for obtaining and documenting informed consent is attached as Exhibit 11. I asked Dr. to define an adverse event. He stated that an adverse event is any that occurs during the administration of the drug substance. He added that if a condition/adverse event is present prior to administration of the drug substance and then the condition presents itself after the administration of the drug substance during the study then that would not be considered to be an adverse event. I asked Dr. what other treatments are offered/done/given at this clinic. He stated that all other treatments are FDA approved treatments such as chemotherapy and radiation therapy. I then asked Dr. to describe the study procedures once the informed consent form is signed. Dr. stated that a patient remains at for days. He stated that during these days. treatment is administered under constant physician care. In addition the patient and/or relative are trained on EIR: Stanislaw R, MD. how to program the IV pump, load the IV pump with the proper amount of study medication. and self-administer the study medication upon their return to their residence. According to Dr. the patient is seen by a senior M.D. during this Wday period. When a patient returns home, a monitoring nurse calls the patient on (4) basis. Once a patient is released to return home, they are required to receive (4) evaluations. Dr. stated that either the patient will return to BRI for an evaluation by a physician knowledgeable about the study or the local co- investigator (patient's physician) will perform the (4) evaluation. Dr. stated that discharge summary is sent to the co-investigator. They are also required to sign an FDA 1572. Statement of Investigator. I asked Dr. how does he assure himself that all adverse events are being reported and/or captured. He stated that when a patient returns home his staff is intelephone contact with the patient. The patient is asked how they have been feeling and for any side effects. All side effects are evaluated for possible relationship with the study medication or if the side effect is attributed to the individual's disease condition. He added that the patient's co--investigator also monitors the patient's progress. I asked Dr. about the patient's dosage level. He stated that the amount of study drug to be receivedladministered to the patient is calculated on a (4) basis. The patient is sent supply. The study medication is sent at I asked how is the medication delivered to the patient. He stated that the study medication is sent via I asked Dr. for the duration of the patient's participation in the clinical study. He stated that they monitor and evaluate the patient's response as per the requirements of the study protocol. Dr. explained that if a patient is found to be a complete responder then they advise the atient to continue intravenous treatment for an additional After the patient is discontinued from intravenous treatment. He then stated that if a patient is declared to be a partial responder, the individual is placed on maintenance therapy with A10 8. AS2-1 (4) Dr. did not specify the time period the patient remains on maintenance therapy but did state that if a patient shows disease progression they are discontinued. I then asked Dr. about the protocol exceptions. He stated that these protocol exceptions are submitted to the FDA for approval. He mentioned protocol exceptions not requiring prior FDA approval include those individuals that have a (4) the protocol requirement and different types of malignancies. He added that all protocol exceptions are submitted to the IRB daily for expedited review. EIR: Stanislaw R. MD., Dr. then stated that with respect to foreiin studies there are currentlyi (4) studies in (4) Reportedly. these studies are under the supervision of the (4) govemment. He also stated that in the past there have been single M.D.'s treating single patients in the (4) but that currently there is no one. He stated that there are no clinical studies being conducted in the (4) Dr. said that the informed consent document will be translated for a (4) patient but that they will sign the English version. He stated that he has individuals on staff that can translate informed consent forms into different languages. For example. (4) A A Dr. stated that survival data is only determined/calculated for certain protocols. He said that for other protocols there is not enough data to calculate survival data. He also mentioned that Karnofsky score data has not been required by the FDA to be reported but that he could present the data if required. On 8-7-01. Dr. _Steven MD.. Medical Officer. HFD-150 joined the FDA inspection team. He presented and issued an FDA 482. Notice of Inspection. to Dr. On 8-8-01, the FDA inspection team was joined by the following: - Lany E. Kun, M.D. - James M. Provenzale. M.D. - Sarah A. Taylor. M.D. They presented credentials and an FDA 482. Notice of Inspection. was issued to The following individuals accompanied us through the inspection and supplied relevant information and also identified individuals that could provide relevant information: - Jaroslaw Paszkowiak. M.D., Supervisor. Department of Medical" Documentation 8- Clinical Trials Supervision. 0 Frank Coffey. Head of Department of Quality Assurance - Barbara Burkhardt, Quality Assurance Monitor 0 Dawn Bradley, Quality Assurance"Regu|atory Assistant EIR: Stanislaw R. M.D.. NOTE: Dr. was available throughout the week to address any queries from the FDA inspection team. Any FDA correspondence should be addressed to Dr. inspection re ative to BRl's compliance with regulations. actions taken by IRB members that could represent a conflict of interest. financial practices that represent billing for the study medication, and possible fabricationladulteration of source documents. - -t -P I 7D copies of IRB provisional approvals for compassionate exceptions for Protocol BT-12 patients. Refer to Exhibit 14. these compassionate exceptions were approved and signed by Drs. Gabor Jurida and Barbara These two individuals are listed as research associates under the Department of Pediatric Oncolo and Department of internal Medicine. respectively. possible conflict of interest by an IRB member. Refer to a copy of a letter from an organization known as "Cancer Coalition--BVO" (Bur2ynsl(4l not contain the tumor measurements that were one by the consultants. -BT-11: The case report form Tumor measurements are attached as Exhibit 60. Dr. Sche|Iinger's case review is attached as Exhibit 61. BT-11 The case report form Tumor measurements and progress notes are attached as Exhibit 62. The consultant's assessments are attached as Exhibit 63. Dr. Burzinski stated that he has been contracting consultant radiologists since approximately 1996. I asked Dr.Bur2inski8 if he reports the consultant radiologists' evaluations, i.e. tumor measurements. He said no. lexpiained to Dr. that all tumor assessments should be reported in the case report forms. He stated that he was unaware of a requirement to report the consultant's tumor measurements. I explained that to include the consultant's assessments would enable complete reporting of all assessments in the case report form. He stated that he understood. l3 EIR: Stanislaw it M.D., 3/6- l0f0l b) The case report forms for atients -BT-23(Exhibit 54), er-23 (Exhibit es), and er-09 do not contain inclusionlexclusion criteria entries. Discussion with Management At the conclusion of the inspection an FDA 483, inspectional Observations, was issued to and discussed with Dr. Also present were Dr. Paszkowiak. Mr. Coffey. Ms. Burkhardt. Ms. Bradley, and Barbara Tomaszewski. Business Manager. first explained that the list of inspectional observations should not be meant to be all inclusive as we had not reviewed all patient files. Dr. stated that he understood. Because the inspectional observations cited specific patient examples. I explained that they should look beyond the inspectional observation when attempting to implement corrective measures and not limit the applicability of corrective actions to the examples cited in each response. I then read each FDA 483 observation. In response to FDA 483 Dr. stated that the FDA allows the acceptance of entry into protocols of individuals other than what is in the protocol. In other words. FDA allowed the entry of individuals into study protocols even though they did not meet the protocol criteria. Dr. also mentioned that FDA allowed a special exemption for those patients listed as part of the inspectional observation to enter a study protocol. Dr. stated he was sure they had documentation on file to cover these patients' enrollment, i.e. patients listed on the inspectional observation. In response to FDA 483 Dr. stated that an SAE is reported only if the event is related to antineoplaston treatment/administration, i.e. possibly or probably related to the study medication. He stated that if an SAE or AE is related to other causes then that is not reported. He added that are usually related to the individual's disease condition andlor previous treatments. Dr. then committed to reporting all in the future. It should be noted that BRl's standard operating procedures CS-002 and CS-003 (Exhibit 38) require to report and SAE's regardless of causality. In response to FDA 483 #3 and Dr. stated that they always incorporate what is asked of them by the FDA and that he would have to review the informed consent documents. In response to FDA 483 Dr. explained that the individual primarily responsible for the inventory of the study medication was out of the country and that he was the individual that could provide an accurate accountability. I asked Dr. Burzinski in his absence who is responsible for the drug accountability. I I4 EIR: Stanislaw R. M.D., explained that shipments (of study medication) continue in his absence, therefore. other individuals should be trained and have full knowledge about the maintenance of study medication accountability. I explained to Dr. that while this individual is gone and because this individual will not be present 100% of the time he should have a back up person responsible for the accountability. He stated that he understood. Because during the review of accountability records I observed one patient - to be listed under the column (Exhibit 49). I asked Dr. about this study protocol. I explained that I had seen in one of the accountability records that a patient was listed under the IND column as being enrolled under an (4) protocol. I asked Dr. (4) was a research study. He said these patients are not in clinical trials. He said they are treated with standard chemotherap regimens. I asked Dr. what did (4) stand for. He said the meant Groupw The stood for patient an stood for various treatments. I asked what treatments did he mean. He said any chemotherapy and specifically mentioned lb) (4) (4) He said of these patients receive chemotherapy. I asked Dr. if there was a study protocol. He said there were many protocols according to the patient's treatment. I asked Dr. if he is collecting data (to support of a future submission). He said he is collecting data because he wants to know how many survive and how they die. He said he wanted to conduct standard treatment(s) in a "more scientific manner" in order to document patient response to "traditional" medical practice. I asked Dr. if he obtained informed consent from these individuals and if so if he had a blank copy of the informed consent form. He said patients do sign a consent form but declined to provide a copy as he felt that protocol was not within the scope of this data audit inspection. He said this is a general practice procedure and not clinical research, therefore, fell under private ractice. I asked Dr. how many individuals had been enrolled in this (4) rotocol. He said he could not give an exact figure but would approximate about individuals. Finally. I asked Dr. if dosage involve ca sules, tablets. intrvenous administrations. He said it involves and (4) administrations. It should be noted that was also on antineoplaston treatment. A "Medicine inventory Form" documents shipments of A10 and AS2-1 to the patient. In addition, progress notes, dated 11-2-00, document that this atient under the protocol was Refer to Exhibit 68. A database listing (Exhibit 69) provided by Dr. asz owtak shows other patients on the (4) protocol. Also note that this database listing (Exhi_bit 69 pacles 7 and 9) documents patients on two other protocols. i.e (4) no (4) EIR: Stanislaw R. M.D., 316-10/0l in response to FDA 483 Dr. stated that he would have to find out why he was not alerted and that these queries should have been corrected immediately. He said that he addresses a query on the same day it is received. That currently he had none pending on his desk referring to the one query dated 8-7-01. I explained that perhaps the one dated 8-7-01 was too soon to have been addressed but could not understand why he was not aware of it. I also explained that the two other queries were old enough that they should have been investigated to determine what exactly had happened with the overdose incident to prevent a recurrence. In response to FDA 483 Dr. stated that he does not specifically remember this case. He added that the FDA does allow for individuals to receive while on study. He mentioned that they must have correspondence for this patient to have been able to receive while on study. He said that he was aware of a few cases like IS one. In response to FDA 483 Dr. explained that the last day of the study is defined as the day a patient receives hislher last dose. He said errors do occur and that errors will be corrected 1 'l (bl b) Referto Exhibit 70. In response to FDA 483 Dr. agreed with the observation and stated that he would begin to report the consultant's evaluations in the case report forms. To conclude Dr. stated that he appreciated the remarks and that he would implement corrections. He also stated that a written response would be submitted. Joel Martinez investigator Dal-DO/San Antonio Resident Post Attachment 1- b) lb) Exhibits: 1- May 1984 Final Judgment of Permanent Injunction 2- CDER correspondence dated 8-14-97 ssoon fud. uring te EIR: Stanislaw R. M.D., 8/6-i0lDl 3- BRI organizational charts 4- List of people that assisted during the inspection 5- Dr. CV 6- List of Complete and Partial Responders 7- Dr. Lewy CV 8- Dr. Bestak CV 9- Dr. Weaver CV 10- Associate M.D.'s CV's and resumes 11- SOP CS-001, Obtaining and Documenting Informed Consent 12- correspondence dated 2-19-01 13- Notes for Patient Chart Review 14- IRB provisional approvals for compassionate exceptions 15- Cancer Coalitoin correpondence 16- Ms. Tomaszewski correspondence 17- Patient ro ress notes 18- Protocol 19- List of patients under protocol (4) . 20- Treatmetn billin A reement 21- PatientHN-02 beneficiary agreement 22- BT-12-01 progress notes 23- Dr. Non-face to face evaluation and management form 24- Patient BT-1 1WHistory and Physical 25- Patient BT-22history and Physical 26- Patient BT-22 History and Physical 27- PatientT-PA-02istory and Physical 28- l??i7"Ci BT-07 progress notes 29-Patient BT-08-W records 30- Patient BT-11 progress notes 31- Patient BT-11 progress notes 32- Patient progress notes 33- Patient BT-21 progress notes 34- Patient 2 progress notes lb) (4) 35- Patient 37- Patient?-UP-02 records 38- SOP CS-O02, routine Adverse Experience reporting 39- Dr. memo dated 8-7-01 40- HFD-1 ax dated 8-1-97 41- Patient PR-04informed consent form 42- HFD-150 fax dated 8-30-97 43- Patientinformed consent form 44- Drug Release Record - 45- Batch 258C drug accountability record 46- Batch 058Bdrug accountability record 47- Batch 823- drug accountability record 48- Batch 80 drug accountability record EIR: Stanislaw R. M.D., 49- Batch 19 drug accountability record 50- BRI discrepancy report dated 11-8-00 51- BRI Query Report dated 4-3-01 52- Query report dated 8-7-01 53- Patient BT-07 records 54- Patient BT-1 7 records 55- Patient BT-1 records 56- Patient BT-20 records 57- Patient LY-06 records 58- Patient (4) records 59- Patient 60- Patient UP-02 records -BT-11 tumor measurements 61- Patient BT-11 records 62- Patient BT-11tumor measurements 63- Patient BT-11 records 64- Patient -BT-23 records 65- Patient 66- Patient -BT-23 records BT-09 records 67- Patient medicine inventory form 68- Patient History and Physical 69- Drug accountability record 70- Dr. memo dated 1-23-01 18 816-10101