[19] – 1995 (6/6/1995) Dr. Michael A. Friedman to Burzynski (3 pgs.)

This page is linked to:
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Critiquing: Dr. Michael A. Friedman, Dr. Mark G. Malkin, Dr. Mario Sznol, Robert B. Lanman, Memorial Sloan-Kettering Cancer Center, Mayo Clinic, Department of Health & Human Services (HHS), Public Health Service, Quality Assurance and Compliance Section, Regulatory Affairs Branch (RAB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment (DCT), National Cancer Center (NCI) at the National Institutes of Health (NIH), Stanislaw Burzynski: On the arrogance of ignorance about cancer and targeted therapies
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https://stanislawrajmundburzynski.wordpress.com/2013/09/08/critiquing-stanislaw-burzynski-on-the-arrogance-of-ignorance-about-cancer-and-targeted-therapies/
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[19] – 1995 (6/6/1995) – Michael A. Friedman, M.D., Associate Director, Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment (DCT), National Cancer Institute (NCI), Department of Health and Human Services (HHS), Public Health Service, National Institutes of Health (NIH) 3 page letter to Burzynski

This letter is intended to respond to the major issues which have been raised in your recent correspondence of 4/20/1995 and 5/16/1995

Your accusations are serious and require comment

I will 1st address the questions you raised about individual patients participating in the NCI-sponsored antineoplaston studies

2 patients were treated at the National Cancer Institute

Patient .26-77-03-9 had evidence of focal glioblastoma multiforme on the biopsy reviewed at the NCI

A different specimen submitted to Dr. Rorke may or may not be relevant

This patient, however, had a brain scan 3 weeks prior to study entry

Patient .27-53-76-5 had a tumor which was 0.8 cm larger than the eligibility criteria dictated

Although pharmacologic data were obtained on both, neither patient is counted in an assessment of response

Both patients had objective tumor progression and are now off study

With respect to the other patients, I am including specific patient summaries from the treating investigators which address your other concerns; in particular, a response to your serious and unfounded statement that patient #196370 was treated in an unethical manner

Also contrary to your statement, you have been sent monthly clinical summaries of these patients since 7/1994 directly from Theradex

(see 3/9/1994 letter)

Having provided this information, I must convey my deep pessimism about the potential for continued interactions with you regarding these trials

Given recent events and your clearly articulated bias that the Mayo Clinic, Memorial Sloan Kettering Hospital and even the National Cancer Institute could not fairly test your product

(please see your letters of 10/26/1993 and 4/20/1995),

I now see a diminishing chance for a productive dialogue with you

Historically, the NCI has demonstrated pragmatism and flexibility in working with a wide variety of individuals and organizations to explore diverse interventions of potential benefit to the cancer patient

However, such a fruitful collaboration may simply not be possible with you

Pg. 2

The decision to suspend the NCI antineoplaston studies was reached by the investigators and the NCI and was explained in our letter of 5/12/1995

(see enclosed)

While we have frequently solicited your advice, we are in no way obligated to obtain your consent

Our interactions with you have been similar to those with pharmaceutical companies or other independent investigators

In the interest of testing antineoplastons, we have consistently considered your advice and recommendations but that in no way cedes control of these studies to you

(please refer to our letters of 7/15/1993, 10/20/1993, and 11/2/1993)

Your insistence on dictating the manner in which we conduct our review of these clinical trials is both presumptuous and inappropriate

The future of these trials rests entirely with the investigators and the NCI, since our primary obligation is to the American public

Recognizing your potential conflict of interest as the developer and the most visible proponent of antineoplastons, we could not responsibly act in any other manner

In contrast to the tenor of your unsupported statements, the NCI bases its position on scientific data

You have stated that you have a vast clinical experience with antineoplastons and we have generally been deferential to your demands despite the lack of substantive data

However, our scientific standards are broadly applied to all studies

The data and level of proof we require from you is much the same as that for other professional collaborators who make such claims

The 7 case records initially examined by the NCI hardly constitute a definition scientific result

It is naive and misleading for you to suggest that the experience of 2 of those patients who had tumors in excess of 5 cm provides adequate proof for all your contentions about tumor size, dose, etc., unless these were the only 7 brain tumor patients from your entire experience who had any hint of benefit

To be precise, in order to responsibly and properly assess your claims and accusations (as per your 4/20/1995 letter), we request that you provide the following information:

1. Exactly how many adult patients with primary brain tumors have you evaluated and treated with antineoplastons?

2. When analyzed by histological type, performance status, prior therapy, concurrent therapy (including chemotherapy), disease size and focality, how many adult brain tumor patients had objective responses?

Please characterize the quality and magnitude and duration of these responses

3. What dose, duration, schedule, and composition of antineoplastons did these patients receive?

Which of these patients benefited objectively?

What toxicities were encountered?

Do you have pharmacokinetic or pharmacodynamic data to support your contention that certain types of brain tumor patients require specific regimens?

4. For these patients, what statistical analyses relate patient or tumor characteristics with exact treatment regimen and outcome?

Pg. 3

If you provide such specific data, we can properly assess your claims

Lacking such information, we cannot

Moreover, your charges that patients received inappropriate care are not supportable without such detailed information

If, after careful consideration, the investigators at Memorial Sloan Kettering and Mayo Clinic do not reopen their studies, it is unlikely that the NCI will attempt to conduct further antineoplaston trials

Any unused antineoplaston material will, of course, be returned to you

Since we can make no judgement about the benefit or toxicity of antineoplastons at this time, we will be interested in the published outcome of peer reviewed studies that you or others may perform

If the NCI investigators choose to continue these studies, you will be so informed

In either circumstance, we will continue to sponsor clinical research of small molecules that may have differentiating properties (such as pure phenylacetate and phenylbutyrate)

cc:

Senator Joseph Biden
Senator Barbara Boxer
Senator Diane Feinstein
Senator Tom Harkin
Senator Barbara Mikulski
Congressman Berkley Bedell
Congresswoman Nancy Pelosi
Dr. Jan Buckner
Dr. Jay Greenblatt
Mr. Richard Jaffe
Dr. Wayne Jonas
Mr. Robert Lanman
Ms. Mary McCabe
Dr. Mark Malkin
Dr. Tony Murgo
Dr. Ralph Moss
Dr. David Parkinson
Dr. Edward Sondik
Dr. Mario Sznol
Dr. Dorothy Tisevich
Dr. Alan Trachtenberg
Mr. Frank Wiewel
Dr. Robert Wittes
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1993 (10/26/1993) – Burzynski to
1994 (3/9/1994) –
1994 (7/1994) – Burzynski to Theradex
1995 (4/20/1995) – Burzynski to
1995 (5/12/1995) – to Burzynski
1995 (5/16/1995) – Burzynski to
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[18] – 1995 (5/16/1995) – Burzynski to Dr. Michael A. Friedman

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Critiquing: Dr. Michael A. Friedman, Dr. Mark G. Malkin, Dr. Mario Sznol, Robert B. Lanman, Memorial Sloan-Kettering Cancer Center, Mayo Clinic, Department of Health & Human Services (HHS), Public Health Service, Quality Assurance and Compliance Section, Regulatory Affairs Branch (RAB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment (DCT), National Cancer Center (NCI) at the National Institutes of Health (NIH), Stanislaw Burzynski: On the arrogance of ignorance about cancer and targeted therapies
——————————————————————
https://stanislawrajmundburzynski.wordpress.com/2013/09/08/critiquing-stanislaw-burzynski-on-the-arrogance-of-ignorance-about-cancer-and-targeted-therapies/
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[18] – 1995 (5/16/1995) – Burzynski letter to Michael A. Friedman, M.D., Associate Director, Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment (DCT), National Cancer Institute (NCI), National Institutes of Health (NIH)

Thank you for your letter of 5/12/1995

You are correct in asserting that I raise issues of ethical misconduct, failure to obtain adequate informed consent and scientific misjudgment

To be exact, my letter points out specific violations of the clinical trial protocol made by the current investigators

I provided careful documentation of some of the most egregious violations, including the removal of a patient from the study who had no increase in tumor size and the inclusion of a patient with tumor pathology that did not meet the entry criteria

It seems possible that, in at least one one of these cases, failure to follow the protocol resulted in the patient’s unnecessary death

In this case, the patient was removed from the study following an MRI dated 5/2/1994

The conclusion of neuroradiologist Jim Cain, MD, is that this MRI shows that the tumor had not grown, and no new tumors are present

As you know, the protocol calls for patients to be taken off treatment if the tumor grows 50% or more, or a new tumor is present

This is, as you point out, a most serious matter, and I was hoping that you could allay my concerns by showing me where they are unfounded

However, your letter conspicuously fails to address them

You also make reference to “numerous factual misstatements” but fail to identify any of them, much less provide documentation to show they are false

Pg. 2

Contrary to another of your statements, I did provide “specific clinical data which support” my contention that patients with large tumors do not respond well to the current protocol

Let me repeat from here

In the 1991 NCI review of 7 brain tumor cases, the only 2 patients with tumor size greater than 5.1 cm were also the only 2 patients to have less than 50% reduction of their tumor

The correlation between large tumor size and failure to respond is obvious

I am happy to learn that the trials have been put on hold

I must insist that they not be re-activated until I am satisfied that new investigators have been found who are capable of following the protocol — the original protocol on which we both agreed

As you know, the protocol was changed without anyone bothering to seek my advice, and certainly without my consent

I am glad that you plan to “thoroughly examine the accusations” I have made

However, this review must not be done by the people responsible for the violations being investigated

This would amount to a whitewash of the whole affair, and is unacceptable

The review must be done by an independent body of experts acceptable to both of us

Otherwise it will be meaningless

I still have not received the complete data on the 1st 5 patients, which was promised in your letter of 4/3/1995

I hope to receive the data soon

I also eagerly await a substantiative response to the points raised in my letter of 4/20/1995

cc:

Senator Joseph Biden
Senator Barbara Boxer
Senator Diane Feinstein
Senator Tom Harkin
Senator Barbara Mikulski
Congressman Berkley Bedell
Congresswoman Nancy Pelosi
Dr. Jan Buckner
Dr. Jay Greenblatt
Mr. Richard Jaffe
Dr. Wayne Jonas
Mr. Robert Lanman
Ms. Mary McCabe
Dr. Mark Malkin
Dr. Tony Murgo
Dr. Ralph Moss
Dr. David Parkinson
Dr. Edward Sondik
Dr. Mario Sznol
Dr. Dorothy Tisevich
Dr. Alan Trachtenberg
Mr. Frank Wiewel
Dr. Robert Wittes
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1995 (5/16/1995) – Burzynski to [15]
(2 pgs.)
1991 NCI review of 7 brain tumor cases
1994 – 5/2/1994 – MRI
1995 (4/3/1995) – Dr. Michael A. Friedman to Burzynski
1995 (4/20/1995) – Burzynski to
1995 (5/12/1995) – Dr. Michael A. Friedman to Burzynski
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[16] – 1995 (4/20/1995) – Burzynski to Dr. Mario Sznol

This page is linked to:
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Critiquing: Dr. Michael A. Friedman, Dr. Mark G. Malkin, Dr. Mario Sznol, Robert B. Lanman, Memorial Sloan-Kettering Cancer Center, Mayo Clinic, Department of Health & Human Services (HHS), Public Health Service, Quality Assurance and Compliance Section, Regulatory Affairs Branch (RAB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment (DCT), National Cancer Center (NCI) at the National Institutes of Health (NIH), Stanislaw Burzynski: On the arrogance of ignorance about cancer and targeted therapies
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https://stanislawrajmundburzynski.wordpress.com/2013/09/08/critiquing-stanislaw-burzynski-on-the-arrogance-of-ignorance-about-cancer-and-targeted-therapies/
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[16] – 1995 (4/20/1995) – Burzynski to Dr. Mario Sznol
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Mario Sznol, M.D., Department of Health and Human Services, National Institutes of Health

Dear Dr. Sznol,

Your letter of 4/3/1995

(copy attached)

does not provide adequate justification for the changes in the protocol for

“Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Advanced
Recurrent Astrocytomas.”

Let me make perfectly clear that, as the discoverer and developer of antineoplastons and the individual with nearly 20 years clinical experience using them, it is my professional opinion that the drugs will not produce substantial benefit in such advanced patients

The current protocol has had success only in patients who have tumors not exceeding 5 cm in diameter and who do not have multiple tumors or leptomeningeal or systemic metastases

As the Senior Investigator of NCI requested, patients should have Karnofsky Performance Status of not lower than 70%

(letter attached)

As I have repeatedly informed you, it is exactly because of the current protocol’s failure to benefit advanced patients that we developed new and more aggressive protocols for such advanced tumors, for example, provides antineoplaston A10 in doses 3 times greater than that specified in the protocol currently being used

In order to make such dosing possible, we are using a much higher concentration of A10 — 300mg/mL instead of 80mg/mL

The dosing schedule being used for such advanced tumors is also quite different

Instead of injections of each antineoplaston every 30 minutes, patients receive a much greater amount every 4 hours

Pg. 2

The acceptance of very advanced brain tumor patients to the current protocol would be highly unethical because there is no realistic chance they will have a meaningful response

The list attached to your letter of 4/3/1995 (enclosed), proves my observation that patients who had tumors substantially larger than 5 cm do not respond well under the current protocol

There were only 2 such patients, with the largest tumor diameter corresponding to 5.5 and. 6.5 cm

Both had less than 50% decrease in the size of their tumors

According to the existing protocol, patients should have more than a 50% decrease in tumor size to be classified as responders

Please bear in mind that the point of this trial is not to prove once again that this protocol does not work in patients with very large tumors, multifocal tumors, and low Karnofsky scores

We have already established this fact

Moreover, the informed consent form as currently written falsely implies that the discoverer of antineoplastons believes such advanced patients may benefit substantially from the current protocol

In fact, I have specifically informed you on several occasions that I do not believe advanced patients will obtain substantial benefit

Please be forewarned that you may face legal liability resulting from these unethical misrepresentations

We are anxiously awaiting the complete data on the 1st 5 patients as promised in your letter of 4/3/1995

Based on the limited information received from Theradex on the 1st 7 cases, we have reason to believe that the protocol has been violated in every case

5 cases have been accepted in violation of inclusion criteria

Due to interruptions in the treatment schedule and the time necessary to escalate the dosage, one of these patients received less than 3 weeks of full dose treatment

Such duration of treatment was not sufficient to show the effectiveness of the therapy

Finally, 2 additional patients were removed from the study and said to have progression of disease when in fact no progression was documented

One of these patients, #4369975, underwent tumor resection 3 weeks after discontinuation of the treatment with antineoplastons

Microscopic examination of the tumor specimen confirmed absence of viable tumor cells

It is clear that what was classified as tumor progression corresponded to extensive necrosis or tumor death

What I thought was especially inexcusable and unethical is that the 30 year old patient #196370, who clearly did not have progression of the tumor, was removed from the study against the criteria for removal listed in the protocol

This patients died a few months later
I strongly believe that if the patient had continued the treatment under the protocol, his life would have been saved

Attached to this letter, you will find a list of

Pg. 3

violations of the protocol

Based on these violations, it is clear that the current investigators are unable to conduct this study under the current protocol

I hereby request that:

1) The National Cancer Institute immediately terminate the current investigators and appoint mew investigators at different medical institutions acceptable to Burzynski Research Institute

2) Patient accrual must cease until such investigators and institutions are appointed

Until you appoint the new investigators, I will provide free treatment and medical care under my supervision as long as necessary to the patients currently being treated under the protocol

SRB/cf

Enclosure

cc:

Senator Joseph Biden
Senator Barbara Boxer
Senator Diane Feinstein
Senator Tom Harkin
Senator Barbara Mikulski
Congressman Berkly Bedell
Congresswoman Nancy Pelosi
Dr. Jan Buckner
Dr. Daniel Eskinazi
Dr. Michael Friedman
Dr. Jay Greenblatt
Mr. Richard Jaffe
Dr. Mark Malkin
Ms. Mary McCabe
Dr. Ralph Moss
Dr. David Parkinson
Ms. Dorothy Tisevich
Mr. Frank Wiewel
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1995 (4/20/1995) – Burzynski to [14]
1995 (4/20/1995) – Burzynski to [15] (3 pgs.)
1995 (4/3/1995) – Dr. Mario Sznol to Burzynski
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[14] – 1995 (3/29/1995) – Burzynski to Dr. Michael A. Friedman (2 pgs.)

This page is linked to:
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Critiquing: Dr. Michael A. Friedman, Dr. Mark G. Malkin, Dr. Mario Sznol, Robert B. Lanman, Memorial Sloan-Kettering Cancer Center, Mayo Clinic, Department of Health & Human Services (HHS), Public Health Service, Quality Assurance and Compliance Section, Regulatory Affairs Branch (RAB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment (DCT), National Cancer Center (NCI) at the National Institutes of Health (NIH), Stanislaw Burzynski: On the arrogance of ignorance about cancer and targeted therapies
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https://stanislawrajmundburzynski.wordpress.com/2013/09/08/critiquing-stanislaw-burzynski-on-the-arrogance-of-ignorance-about-cancer-and-targeted-therapies/
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[14] – 1995 (3/29/1995) – Burzynski to Dr. Michael A. Friedman (2 pgs.)
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Michael A. Friedman, M.D., Associate Director,Cancer Therapy Evaluation Program, Division of Cancer Treatment, NCI, National Institutes of Health

Dear Dr. Friedman,

It has been brought to my attention that the protocol

“Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Advanced Recurrent Malignant Astrocytomas”

has been amended to accept patients with tumors measuring over 5 cm in diameter, multiple tumors, or with leptomeningeal or systemic metastases

Another change involves lowering of the Karnofsky Performance Status score to 60%

You assured me in your letter of 11/2/1993 that

“The dose and schedule will be modified exactly as you require”

and

“The eligibility criteria will be modified to accept only patients with Karnofsky Performance Status of 70% – 100%

I am outraged that without my knowledge Memorial Sloan-Kettering Cancer Center with NCI’s permission changed the protocol

Treatment of patients with tumors larger than 5 cm, with multiple tumors, and leptomeningeal spread or distant metastases will require a different protocol with a different schedule and different dosages

the use of the existing protocol for such very advanced brain tumor patients will only expose them to unnecessary risks without giving them substantial benefit

I hereby request that the amendments described above be cancelled immediately and the original protocol be used for the treatment as promised in your letter of 11/2/1993

We will be glad to propose a different protocol for patients with larger and multiple tumors and meningeal involvement

In addition, the procedure we agreed upon calls for a thorough review by us of the 1st 5 patients as soon as they are accrued

Your last annual report indicates

Pg. 2

that you had accrued that number of patients 6 months ago

As a result, the review of data is long overdue

Please send us the complete records of the 1st 5 patients so that we may review them as specified

Please do not accrue any more patients until this data has been sent and our review completed

SRB/cf

cc:

Dr. Jan Bruckner
Dr. Michael C. Christian
Dr. Jay Greenblatt
Dr. Mark Malkin
Ms. Mary McCabe
Dr. David Parkinson
Dr. Mario Sznol
Ms. Dorothy Tisevich
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1993 (11/2/1993) – Dr. Michael A. Friedman to Burzynski
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[9] – 1993 (11/2/1993) – Dr. Michael A. Friedman to Burzynski

This page is linked to:
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Critiquing: Dr. Michael A. Friedman, Dr. Mark G. Malkin, Dr. Mario Sznol, Robert B. Lanman, Memorial Sloan-Kettering Cancer Center, Mayo Clinic, Department of Health & Human Services (HHS), Public Health Service, Quality Assurance and Compliance Section, Regulatory Affairs Branch (RAB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment (DCT), National Cancer Center (NCI) at the National Institutes of Health (NIH), Stanislaw Burzynski: On the arrogance of ignorance about cancer and targeted therapies
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https://stanislawrajmundburzynski.wordpress.com/2013/09/08/critiquing-stanislaw-burzynski-on-the-arrogance-of-ignorance-about-cancer-and-targeted-therapies/
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[9] – 1993 (11/2/1993) – Michael A. Friedman, M.D., Associate Director, Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment, National Cancer Institute (NCI), Department of Health & Human Services (HHS), Public Health Services, National Institutes of Health (NIH) to Burzynski [3 pgs.]

Department of Health and Human Services, Public Health Services, National Institutes of Health

Dear Dr. Burzynski:

With regard to your letter of 10/26/1993, you specifically state

“The medicine will be sent to you immediately once you make the corrections to the protocol that we have requested”

We have substantial factual disagreements and scientific reservations with many of the comments made in your 10/26/1993 letter, including your preposterous claim that the NCI wasted 8 months

Nonetheless, we will accede to all the modifications that you have stipulated

We do so because we are committed to beginning the clinical studies as quickly as possible

We presume that these are your final comments, since all the changes will have been made and we will have addressed all of your concerns regarding these studies

The revised protocol will be sent to you as soon as it is received from the investigators

Based on the promise in your letter, we expect that the drug will be shipped to the NCI repository the next day

The changes to made to the protocol are as follows:

1. The dose and schedule will be modified as exactly as your require

We believe this to be the dose and schedule found in your protocol BT6, with dose escalation and maximum dose guidelines for adults clarified in your letter of 10/13/1993

2. The Memorial study, as written, has 2 separate components, one for patients with glioblastoma multiforme and one for patients with anaplastic astrocytoma

Accrual to each stratum proceeds independently, and analyses of each stratum is separate

However, we will ask the investigators from Mayo Clinic to join the Memorial study, rather than conducting an independent trial

This will effectively evaluate on the one hand patients with glioblastoma multiforme, and on the other hands those with anaplastic astrocytoma

Pg. 2

Patients with either disease will be enrolled at both Memorial and Mayo sites

This modification has 2 advantages — it limits total accrual to 35 patients per histology, as you request; and it accelerates accrual, since each institution can enter both types of patients on the studies

3. As you stipulated, Fleming’s original statistical design will be used utilized
15 patients will be entered independently to each stratum; for each stratum, if there is 1 response, accrual will proceed to a total of 35 patients

Thus total accrual will be 70 patients if both strata proceed past the 1st stage

(the initial 15 patients per histology)

4. According to your wishes, all scans for tumor measurements and laboratory test will be performed within 7 days of initiating protocol therapy, rather than the standard 14 days now specified in the protocol

5. The eligibility criteria will be modified to accept only patients with a Karnofsky performance status of 70-100%

6. As you require, the protocol response criteria will be based on objective tumor measurements and will not include assessment of neurologic status

Neurologic status will be evaluated separately

7. In accordance with your letter, we will arrange a review of data after accrual of the 1st 5-6 patients, which should occur 6 months after the study has been initiated

This should be sufficient to assure that the conduct of the study is satisfactory

The Theradex database is also available to precisely determine if the conduct of the study has followed protocol guidelines; the study centers will also be audited on-site by Theradex (independent contractors) every 3 months

In your letter you express concern regarding what you perceive to be bias against alternative treatments by Mayo Clinic and Memorial investigators

Please note that the investigators participating in the antineoplaston studies volunteered to do so because of the findings of the NCI review of your best case series

To my knowledge none of the participating investigators have expressed (publicly or privately) a position for or against Antineoplastons

Both institutions have a distinguished record in clinical investigations, and have been leaders in subjecting all treatments (including alternative interventions) to fair and objective clinical research

We are confident that credible clinical studies will be conducted

Pg. 3

Finally, if even after modifying these studies in accordance with your stated wishes, you are unwilling to supply the antineoplaston materials, please inform me as quickly as possible

We will then seek alternative sources of this family of molecules for proper clinical evaluation

Michael A. Friedman, M.D., Associate Director, Cancer Therapy Evaluation Program, Division of Cancer Treatment, NCI

cc:

Dr. Samuel Broder
Dr. Jan Bruckner
Dr. Bruce Chabner
Dr. Jay Greenblatt
Dr. Joseph Jacobs
Dr. Mark Malkin
Ms. Mary McCabe
Dr. David Parkinson
Dr. Mario Sznol
Ms. Dorothy Tisevich
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1993 (11/2/1993) – Dr. Michael A. Friedman to SRB [9]
1993 (11/2/1993) – Dr. Michael A. Friedman to Burzynski [14]
1993 (11/2/1993) – Dr. Michael A. Friedman to SRB [19] (3 pgs.)
1993 (11/2/1993) – Dr. Michael A. Friedman to Burzynski [24]
1993 (10/13/1993) – Burzynski to Dr. Michael A. Friedman
1993 (10/26/1993) – Burzynski to Dr. Michael A. Friedman
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[8] – 1993 (10/26/1993) – Burzynski to Dr. Michael A. Friedman

This page is linked to:
=====================================
Critiquing: Dr. Michael A. Friedman, Dr. Mark G. Malkin, Dr. Mario Sznol, Robert B. Lanman, Memorial Sloan-Kettering Cancer Center, Mayo Clinic, Department of Health & Human Services (HHS), Public Health Service, Quality Assurance and Compliance Section, Regulatory Affairs Branch (RAB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment (DCT), National Cancer Center (NCI) at the National Institutes of Health (NIH), Stanislaw Burzynski: On the arrogance of ignorance about cancer and targeted therapies
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https://stanislawrajmundburzynski.wordpress.com/2013/09/08/critiquing-stanislaw-burzynski-on-the-arrogance-of-ignorance-about-cancer-and-targeted-therapies/
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[8] – 1993 (10/26/1993) – Burzynski to Dr. Michael A. Friedman
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Dear Dr. Friedman,

In response to your letter of 10/20/1993, it is difficult for me to understand why the entire 1st page of your letter is used to discuss the simplest issue:

that adults should use a different dosage than that used for children

Since you agreed to the study procedure of Protocol BT-6 as recommended in my letter of 6/9/1993, we have not requested any changes in the structure of treatment which was accepted by Memorial-Sloan-Kettering Cancer Center (MSKCC)

As you confirmed in your letter of 10/20/1993, you know very well that since 4/1/1993 of this year my recommended dosage of Antineoplaston AS2-1 for adults is 0.4g/kg/24h

Again, I confirmed that this is the right dosage for adults in my letter to Dr. Shoemaker of 8/24/1993

Yet, for no apparent reason, you insist on using in the adult treatment protocol the dosage 0.6g/kg/24h which I recommend for children

It is generally known that a child’s body weight is much lower than that of adults

This should be reflected in the escalation of the dosages

My recommendation as to how to escalate the dosages for adults was submitted to the NCI on 6/4/1992

Yet, for no apparent reason the MSKCC protocol, which is designed for adults, escalates the dosages in the small increments recommended for children

The principle behind dose escalation is to accomplish the maximum dosage in 3 to 5 days, not 3 to 4 weeks, which would expose the patient to the unnecessary risk of tumor progression

I appreciate very much that you have finally decided to follow my recommendation regarding dosage and dosage escalation

Regarding the number of patients to be treated at MSKCC, the contradictory, incomplete, and inconsistent information is being supplied by you

The MSKCC’s protocol of 4/16/1993, 7/13/1993, and 8/30/1993 describe the treatment of 35,

Pg. 2

but not 70 patients

(please see paragraph 12.1, pg. 10 of the protocol, which is attached)

It was our understanding that 35 patients would be treated at MSKCC and at the Mayo Clinic

I never agreed for the treatment of 70 patients at MSKCC

Since I have to produce the medicine for the trial and pay for it, it is vitally important to me to know how many patients will be treated

The treatment of an additional 35 patients may cost up to 2 million dollars

Contrary to the information given by NCI that we received the money for the production of medicine, this money went apparently into a “black hole”

(“Black Holism,” The Village Voice, 7/29/1993, enclosed)

We have received none of the money which the Office of Alternative Medicine gave to the NCI for funding the trials with our medicine

Contrary to the opinion expressed in your letter, we see no reason for modifying Fleming’s Phase II clinical trial design and introducing more stringent than usual criteria for response evaluation

We request that Fleming’s original design be used, which calls for the initial treatment of 15 patients with at least one responder, instead of 20 patients and 2 responders

Given the fact that there is no existing treatment effective in this type of cancer, one responder in 15 is certainly significant and would be reason enough to expand the trial

I found your your requirement for 14 days to complete scans and laboratory tests prior to treatment very interesting

It is a very well known fact that glioblastoma multiforme is such an active tumor that if 2 weeks elapses from the time of the scan and the beginning of treatment, the tumor may increase by more than 50%

This means that even before the patient begins treatment, he can be classified as an increasing disease case

In most of the hospitals in the U.S., including out tiny clinic, all pretreatment tests including the scans can be done in one day

Therefore, I insist that the pretreatment evaluation, including brain scans, be done within 7 days from the time treatment begins

Regarding the Karnofsky Performance Status (PS), it is unclear to me why you have backed off from your own recommendation in your letter of 5/5/1993 (copy attached) that “patients with Karnofsky PS of below 70% should be excluded”

I am requesting that as recommended by NCI, the patient’s PS should be 70% to 100%

I agree that both scan data and neurological assessment can be described in the analysis of response, but the decision of how to classify response should be based on tumor measurements alone

All of these patients will have been extensively treated before

As the result of previous neurotoxic treatments, a number of these patients will deteriorate neurologically even if the Antineoplastons eradicate the

Pg. 3

tumor

The purpose of the protocol is to evaluate the antitumor effect, not to prove that Antineoplastons can repair brain damage resulting from chemotherapy and radiation

In this 1st independent study with Antineoplastons, in order to assure that patients will derive the most benefit from the treatment, it is critically important to schedule more frequent evaluations of the data than waiting until after the accrual of 14 patients, i.e. waiting 9 months

(Based on an accrual of 2 patients per month, if we wait until 14 patients are accrued and treated, 9 months will pass before the 1st evaluation takes place)

Therefore, I request that reviews of the studies be performed after the treatment of each group of 5 patients, i.e. after 6 months

I agree, however, that you will provide the Theradex printout to us as you receive it

In addition to patient welfare, there is another reason for more frequent patient evaluations

As you stated in your letter, I have no doubt that the investigators at MSKCC have extensive experience treating glioma

However, MSKCC is known to be biased against Antineoplastons

At least 3 researchers associated with MSKCC published willful misrepresentations and distortions about Antineoplaston research

Because of the controversial nature of the upcoming Antineoplaston clinical trials, it is essential that they are conducted in a manner beyond any suspicion of bias

Contrary to the opinion expressed in your letter, NCI is responsible for the trial’s delay

As you well know, the NCI selected an MSKCC investigator in 9/1992

In spite of our repeated requests, 8 months were waisted before the NCI produced the 1st draft of the protocol

As promised in my letter to you of 11/11/1992, the supply of Antineoplastons has been prepared and was shown to Ms. Mary McCabe of NCI during the site visit on 2/9/1993

The medicine was ready to be released pending final approval approval of the labels by the FDA and our final QC inspection

The medicine will be sent to you immediately once you make the corrections to the protocol that we have requested

Since you mentioned that patient recruitment has begun already, I would be glad to accept these patients immediately under my care and offer them free medicine as we wait for the protocol to be revised and the treatment at MSKCC to begin

The MSKCC protocol in its current form would threaten the welfare of these patients

In your letter you stated that your mission is to find and develop better therapies for cancer patients, and that your only obligation is to those patients

However, the way

Pg. 4

you proceed leads me to question that for the following reasons:

1) Out of numerous cancer treatment centers, you selected 2:

MSKCC and Mayo Clinic, which are known to be strongly biased against alternative treatments

In the past doctors associated with MSKCC have voiced strong opposition to Antineoplaston therapy and have published articles full of misrepresentations and distortions

2) The protocol approved by you will allow the disease to progress between the pretreatment evaluation and the beginning of treatment

3) Due to the slow escalation of dosages, patients will most likely have marked increase of tumor size beginning the treatment at the correct dosage level

4) In spite of my numerous requests (letters of 4/29/1993, 6/9/1993, and 8/24/1993) to proceed following the guidelines of the NCI’s Decision Network on 12/2/1991 to have a separate clinical trial for glioblastoma multiforme and anaplastic astrocytoma, you continue to combine both types of tumors together

Even in your most recent stratification strategy submitted to the FDA, you are planning to treat initially 20 patients without specifying whether those 20 patients are per each stratum (glioblastoma vs. anaplastic astrocytoma), or whether this initial group of 20 patients consist of a mixture of glioblastoma and anaplastic astrocytoma

If the latter is the case, then we can expect that among these 1st 20 patients, most will have glioblastoma, which is more common and more difficult to treat

In case of treatment failure in these 20 patients, it will be easy to make the statement that Antineoplastons do not have therapeutic effect in both tumor categories

5) The protocol now states in paragraph 10.2, 10.3, and 10.4 that the objective decrease of tumor size is not enough to be considered a true response to treatment, that there must also be improvement in neurological function

As I explained in my letter of 10/13/1993 to Dr. Greenblatt, it is not unusual in my practice to see patients whose tumor has disappeared, but who have deteriorated neurologically as the result of delayed toxicity from radiation therapy and chemotherapy

Since these patients in the MSKCC study have been pretreated, and since there has been no indication that anything, including Antineoplastons, can repair brain damage caused by chemotherapy and radiation, I request that the criteria including restored neurological functioning be removed from paragraphs 10.2, 10.3, and 10.4 of the protocol

Pg, 5

6) Finally, by limiting our access to the data and not allowing review until after the 1st 14 patients have been treated, it would be easy to deviate from the protocol and supply inadequate treatment, and then claim that due to the the failure of the 1st 14 patients it would be a waste of the taxpayers money to proceed with further treatment

Your final statements that you are ready to proceed with the treatment with Antineoplastons without our participation caught me by surprise

It is hard to imagine that a Federal employee would consider patent infringement, thus infringing on the patent rights of thousands of our shareholders

Once again, I urge you to take our requests seriously, honor the guidelines of the NCI’s Decision Network on 12/2/1991, and make proper corrections to the protocol, so that objective clinical studies can begin immediately

In the meantime, I would be glad to treat for free all the patients presently recruited, and will submit progress reports weekly for the NCI’s review and evaluation

SRB/cf

cc:

Senator Joseph Biden
Senator Barbara Boxer
Senator Dianne Feinstein
Senator Tom Harkin
Senator Barbara Mikulski
Congressman Berkley Bedell
Congresswoman Nancy Pelosi
Dr. Samuel Broder
Dr. Jan Buckner
Dr. Bruce Chabner
Dr. Daniel Eskinazi
Dr. Jay Greenblatt
Dr. Joseph Jacobs
Dr. Mark Malkin
Ms. Mary McCabe
Dr. David Parkinson
Dr. Mario Sznol
Ms. Dorothy Tisevich
======================================

======================================
1993 (10/26/1993) – SRB to [5]
1993 (10/26/1993) – SRB to [14]
1991 (12/2/1991) – guidelines of the NCI’s Decision Network [5 Pgs.]
1992 (6/4/1992) Burzynski to NCI
1992 (9/1992) – NCI selected MSKCC investigator
1992 (11/11/1992) – Burzynski to Dr. Michael A. Friedman
1993 (2/9/1993) – NCI Mary McCabe site visit
1993 (4/1/1993) –
1993 (4/16/1993) – MSKCC protocol
1993 (4/29/1993) – Burzynski to
to proceed following the guidelines of the NCI’s Decision Network on 12/2/1991
1993 (5/5/1993) – Dr. Michael A. Friedman to Burzynski
1993 (6/9/1993) – Burzynski to
to proceed following the guidelines of the NCI’s Decision Network on 12/2/1991
1993 (7/13/1993) – MSKCC protocol
1993 (7/29/1993) – “Black Holism,” The Village Voice
1993 (8/24/1993) – Burzynski to Dr. Dale Shoemaker
to proceed following the guidelines of the NCI’s Decision Network on 12/2/1991
1993 (8/30/1993) – MSKCC protocol
1993 (10/20/1993) – Dr. Michael A. Friedman to Burzynski
======================================

[7] – 1993 (10/20/1993) – Dr. Michael A. Friedman to Burzynski (4 pgs.)

This page is linked to:
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Critiquing: Dr. Michael A. Friedman, Dr. Mark G. Malkin, Dr. Mario Sznol, Robert B. Lanman, Memorial Sloan-Kettering Cancer Center, Mayo Clinic, Department of Health & Human Services (HHS), Public Health Service, Quality Assurance and Compliance Section, Regulatory Affairs Branch (RAB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment (DCT), National Cancer Center (NCI) at the National Institutes of Health (NIH), Stanislaw Burzynski: On the arrogance of ignorance about cancer and targeted therapies
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https://stanislawrajmundburzynski.wordpress.com/2013/09/08/critiquing-stanislaw-burzynski-on-the-arrogance-of-ignorance-about-cancer-and-targeted-therapies/
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[7] – 1993 (10/20/1993) – Dr. Michael A. Friedman to Burzynski (4 pgs.)

Michael A. Friedman, M.D., Associate Director, Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment, National Cancer Institute (NCI), Department of Health & Human Services (HHS), National Institutes of Health (NIH) letter to Burzynski [4 Pgs.]

Dear Dr. Burzynski:

This letter is in response to your correspondence of 10/11/1993

(addressed to Dr. Sznol)

and of 10/13/1993

(to Dr. Greenblatt)

Your most recent comments regarding the approved study of antineoplastons in adults brain tumor patients, faxed to Dr. Greenblatt on 10/13/1993, come as quite a surprise

Particularly confusing are your comments regarding dose and schedule of antineoplastons proposed in that study (your comment #1)

Originally the dosage and schedule for this study was based on your protocol BT4

This version of BT4 was entitled,
“Therapy of high-grade glioma with continuous infusions of antineoplastons A10 and AS2-1”,
and was accompanied by 12 case histories

(patients with either anaplastic astrocytoma or glioblastoma multiforme treated apparently according to BT4)

In your letter of 4/26/1993, however you stated that protocol BT4 was only for low-grade gliomas

Furthermore, you noted that protocols BT5 or BT6 should be used for patients with anaplastic astrocytoma and gliobastoma multiforme

In that same letter (4/20/1993), you noted that AS 2-1 was tolerated well at doses of .5 gm/kg/24h by adult patients when administered in intermittent injections (this is method of administration in BT6 and in the IND study)

You stated that if given by continuous infusion, adults would experience increased sleepiness and tiredness, and specifically stated that the dosage of AS2-1 by continuous infusion for low-grade gliomas should be reduced to 0.4 g/kg/24h

You did not provide data to support these assertions, nevertheless, based on these comments and our review of the protocols BT4, BT5, BT6, we instructed the investigators to revise their protocol in accordance with your instructions

In the Consensus Review sent 5/5/1993, we instructed the Memorial Sloan Kettering investigators to pattern their protocol according to BT5, which was written for both children and adults
We specifically pointed out that BT6 was written for children

In your letter of 6/9/1993, regarding our Consensus Review, you specifically asked that the investigators use the treatment program according to BT6, knowing that the Memorial protocol was for adults with AA and/or GM

You did not at any time mention that dose escalation should be modified for adults, or mention any dose limitation for adults given the intermittent as specified in the BT6 protocol

Page 2

Your concerns regarding dose limitation in the previous letter appeared to be related to continuous infusion administration

The letter of 6/9/1993, contained only 4 comments and at that time you had both the protocol and Consensus Review in your possession

We transmitted your letter of 6/9 directly to the investigators, and all your requested changes were made

Our sincere efforts to attempt to duplicate your findings and follow your recommendations are frustrated by receiving contradictory, incomplete, and inconsistent information from you

We have, at multiple points in the protocol development, solicited your input and followed your guidance in getting recommended dose escalation and modification guidelines for adults

Please note that, one last time, we will ask the investigator to revise the protocol with regard to dose and schedule in compliance with your latest letter

However, we plan that the study will begin immediately and this will be the last such modification

Although you have not provided data to support each of your specific recommendation, we have incorporated them

With regard to comment #2 of your Fax of 10/13/1993, you have misinterpreted the protocol

The total number of potential patients is 35/stratum, (ie a total of 70 patients) allowing for an adequate Phase II evaluation of each group of patients

With regard to the statistical section, your #3 comment, there is little reason to assume that the modified Fleming design currently used in the protocol for the first stage of accrual is less appropriate than a design using 15 patients in the first stage

If the true response rate of the antineoplastons is 20% (standard criteria for activity in all our phase II trials considered worthy of further study), the chance of proceeding to the second stage of accrual with the current design is 93.1%

The chance of proceeding to the second stage using 15 patients in the first stage of accrual is 96.5%

These differences are not considered meaningful

With regard to your comment #4, we wish to maintain the standard clinical trials methodology used to evaluate new agents

We know of no evidence that obtaining a brain scan within 7 days of treatment versus within 14 days of treatment will in any way affect the evaluation of activity of a drug in this disease

The protocol clearly states that scans must be obtained within 2 weeks of study entry

Please also note that the practical difficulties in scheduling scans and completing the pretreatment work-up in just one week; the costs of repeating tests simply to meet this artificial deadline could not be justified and probably would not be covered by insurance companies

With regard to your point #5, (performance status) your own protocols allow patients with Karnofsky performance status of 60

We see no reason to demand a more stringent entry criteria for performance status than you have employed for your own patients

Page 3

With regard to your point #6, the use of neurologic status as well as CT scans/MRI findings to determine response, this was suggested to the investigators in our Consensus Review of 5/5/1993

You made no comment regarding this in your letter of 6/9/1993

This use of neurologic function as an additional criteria to determine response is an objective measurement and is standard among protocols we sponsor for glioma patients . .

It is scientifically acceptable to include the criteria for response as currently written in the protocol

At analysis, both scan data and objective neurologic assessment can be described

With regard to your letter of 10/11/1993, concerning data reviews, we are satisfied that reviewing the data after accrual of the first 14 patients/stratum is sufficient

We share your concerns about patient safety but believe that these investigators have extensive experience treating glioma patients, are superb and careful physicians, and have extensive experience administrating a range of investigational agents to these patients

Furthermore, the patients will be followed carefully, and dose reductions for expected toxicities will be carried out as specified in the protocol

Nevertheless, your experience with the agents is valuable and the availability of your guidance is much appreciated

If necessary, we will arrange a conference call at the end of treatment of the first 5 patients, or sooner if problems occur

Your participation in such a conference call, if necessary, would be welcome

We will provide the Theradex (CTMS) printout to you on a monthly basis as we receive it

We do not believe it is practical or necessary to supply data on an every 2 week basis

The most important unresolved issue at this time is that we are still waiting to receive the promised supply of antineoplastons to conduct these studies

Your letter of 11/5/1992, guaranteed a supply of the antineoplastons by 3/31/1993

(see attached)

As of today we still have not received it

Believing that you would be shipping drug to the NCI, and since the protocol is approved at Memorial Sloan Kettering, recruitment of patients has begun

As you point out, these patients have aggressive disease, and cannot afford to wait to begin treatment

We are prepared to try to assist you in meeting this commitment, but we know of no obstacle here at NCI

We urgently request, again, that you ship the drug immediately

Please be aware that our mission is to find and develop better therapies for cancer patients, and our only obligation is to those patients

Our agreement to pursue these studies with antineoplastons was based on suggestive evidence

Page 4

of activity noted in your best case studies

If you are unable or unwilling to provide the antineoplastons in the near future, we will pursue alternative sources to procure the drug or its active components, and will proceed with a clinical development plan to determine whether these chemicals have activity and are beneficial for patients

Michael A. Friedman, M.D., Associate Director, Cancer Therapy Evaluation Program, Division of Cancer Treatment, NCI, Department of Health and Human Services, National Institutes of Health

cc:

Dr. Samuel Broder
Dr. Jan Buckner
Dr. Bruce Chabner
Dr. Jay Grabnett
Dr. Joseph Jacobs
Dr. Mark Malkin
Ms. Mary McCabe
Dr. David Parkinson
Dr. Mario Sznol
Ms. Dorothy Tisevich
——————————————————————

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1993 (10/20/1993) – Dr. Michael A. Friedman to Burzynski [8]
1992 (11/5/1992) – Burzynski ANP 3/31/1993
1993 (4/20/1993) – Burzynski (4/26/1993)? in that same letter
1993 (4/26/1993) – Burzynski
1993 (5/5/1993) – Consensus Review
1993 (6/9/1993) – Burzynski re Consensus Review
1993 (10/11/1993) – Burzynski to Dr. Mario Sznol
1993 (10/13/1993) – Burzynski fax to Dr. Jay Greenblatt
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