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

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
[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)


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

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

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

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
[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


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

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