The Observer has deigned to respond to the concerns raised over the last couple of weeks in relation to the rather uncritical coverage it afforded the controversial Burzynski Clinic and, to be perfectly honest, there is very little I can say by way of a response to the Observer’s Readers’ Editor, Stephen Pritchard, that Andy Lewis hasn’t already covered in spades over at The Quackometer. Andy’s response to The Observer comes highly recommended (of course) not least for the economy with which he nails the central issue that the paper has clearly chosen to overlook:

Written by Stephen Pritchard, the Readers’ Editor, the response attempts to justify its coverage and blames bloggers for “aggression, sanctimony and a disregard for the facts”. It is a disgraceful and self-serving response. Pritchard claimed their story was one of “courage and generosity”. No it was not. It was a story of exploitation of courage and generosity. The Observer still fails to understand this.

So, is there anything more to be said on the subject of the Burzynski Clinic?

Well, yes, there is – because while I was reading Andy’s response I had one of my occasional Colombo moments, the creeping sensation that somewhere in all this I’d missed a potentially important detail, the kind of detail that leaves you thinking ‘Oh, There is just one more thing…’

And that one more thing is..?

Let’s go right back to start and The Observer’s original article about Bettie Bainbridge, which gives this description of her condition:

But after a scan, she was diagnosed with a tumour on her brain stem. It’s called Diffuse Intrinsic Pontine Glioma (DIPG). And it’s known as the worst type of brain cancer. A doctor described it as “the worst kind of tumour in the worst place”.

This is an incredibly rare illness: only about 40 children are diagnosed with it every year in Britain. The cause is unknown but it is not genetic. If you look it up on the internet, all the statistics are stacked against Billie. It’s an aggressive tumour and it’s in the most delicate place. It’s too dangerous to operate on because many of the brain’s vital functions are located in the stem. So all that can be done is to try to reduce it using radiotherapy.

The prognosis is complicated. Many of the children with these tumours have a life expectancy of around a year to 18 months. Is it impossible for her to survive? No, as it turns out. Sam and Terri very quickly found out about a pioneering treatment at the Burzynski Clinic in Texas for children with DIPG. The estimated cost is £200,000. It is not available in this country, it is new and there are no guarantees. When you are faced with a decision like that, what can you do? It’s like Monopoly money and when we realised we would have to raise this amount, it seemed ridiculous. Especially as there’s only a slight chance that the treatment might work.

To this, Stephen Pritchard’s article add the following additional background details:

Luke Bainbridge told me: “From the start, Billie’s parents knew this treatment was experimental and has attracted scepticism but they were encouraged by the fact that the trials at the clinic are approved by the US Food and Drug Administration and that Billie would still be monitored by her specialists in the UK. Her parents know it is unproven, but there are other families in this country who were told by their hospital that their condition was terminal and nothing could be done for them, but were then treated at the clinic and survived. Knowing this, Billie’s parents felt they couldn’t sit back and do nothing if there was a small chance this treatment would save her life.”

According to Pritchard this point is ‘being lost in the vitriol that is flying around the internet’ when, in fact, it isn’t. Bloggers who’ve written about the Burzynski Clinic over the course of this last week – myself included – are keenly aware of the extent to which ‘FDA approved’ can, in some cases, confer a sense of legitimacy that is out of all proportion to reality of exactly what it the FDA have actually approved.

What I particular want you to bear in mind, as we move on, is the description of Billie Bainbridge’s condition. She has been diagnosed with Diffuse Intrinsic Pontine Glioma, which is a tumour on her brainstem for which the prognosis is not good – and if you’re at all unsure where the brainstem is, then if you runs your fingers lightly up the back of your own neck, you’ll quickly come to a large bump of bone at the point at which the spine meets the base of your own skull; the brainstem is pretty much there, although, obviously, its on the inside of the skull.

Working on the entirely reasonable assumption that the Bainbridge family will have turned to Dr. Google for advice while looking for treatment option for their daughter, its highly likely that they will have come across the following press release on the Burzynski Clinic’s own website:

Burzynski Research Institute Gets SPA Clearance from the FDA to Initiate Pivotal Phase III Trial of Combination Antineoplaston Therapy and Radiation Therapy

Study to Evaluate Children with Newly-Diagnosed Diffuse Intrinsic Brainstem Glioma

HOUSTON, TX – January, 13, 2009 – The Burzynski Research Institute, Inc. (BRI) today announced that it has reached an agreement with the U.S. Food and Drug Administration (FDA) that enables the company to move forward immediately with a pivotal Phase III clinical trial of combination antineoplaston therapy plus radiation therapy in patients with newly-diagnosed, diffuse, intrinsic brainstem glioma. Antineoplaston therapy (ANP) uses a synthetic version of naturally occurring peptides and amino acid derivatives found in the human body to target and control cancer cells without destroying normal cells. The agreement was made under the FDA’s Special Protocol Assessment (SPA) procedure and means that the design and planned analysis of the Phase III study is acceptable to support a regulatory submission seeking new drug approval.

The full statement includes a concluding statement for investors, which indicates that this statement was released to the financial markets.

Clearly, to a family seeking treatment options for a child with DIPG, this statement would appear to be manna from heaven but, as invariably seems to be the case when it comes to the Burzynski Clinic, things are not quite that straightforward.

This particular release dates to 14 January 2009, and only a fortnight later, the clinic was back on the business newswires to announce that it had partnered with Premier Research to manage its Phase III trial:

HOUSTON–(BUSINESS WIRE)–The Burzynski Research Institute, Inc. (BRI) today announced that it has partnered with Premier Research, a global clinical research services provider, to initiate and manage a pivotal Phase III clinical trial of combination antineoplaston therapy (ANP) plus radiation therapy in patients with newly-diagnosed, diffuse, intrinsic brainstem glioma.

Premier Research is currently conducting a feasibility assessment. A number of academic centers in the U.S. and Europe will be considered, including Houston-based academic centers specializing in the treatment of pediatric brain tumors. To date, Premier has secured interest and commitment from a number of sites selected. Upon completion of this assessment, a randomized, international Phase III study will commence.

Winding things forward to May 2009, and the Burzynski Research Institute has two more announcements to issue to the business newswires:

6 May 2009

Burzynski Research Institute Announces Positive Results of Phase II ANP Clinical Trial

HOUSTON–(BUSINESS WIRE)–The Burzynski Research Institute (BRI) announced today positive safety and efficacy results in its Phase II clinical trial of Antineoplaston A10 and Antineoplaston AS2-1 therapy (ANP therapy) in children with optic pathway glioma (OPG). The results were presented to the FDA in the Request for End of Phase II Meeting Briefing Package (ANP in OPG), to be discussed at a meeting with the FDA on May 7, 2009. The FDA responded to the questions in the Briefing Package and issued additional comments before the meeting. The answers and comments were clear, and the meeting was cancelled since further discussion was not required. Based on preliminary responses and additional comments from the FDA, a protocol for a Phase III randomized trial with ANP in OPG will be prepared and submitted for FDA Special Protocol Assessment (SPA) to secure agreement on the design of a Phase III trial to serve as an efficacy claim in a New Drug Application (NDA).

11 May 2009

Burzynski Research Institute Presents Positive Results From Phase II Trials of ANP for Inoperable Brainstem Glioma at the Congress

HOUSTON–(BUSINESS WIRE)–The Burzynski Research Institute, Inc. (BRI) announced today that it made three presentations of the results of phase II trials and mechanism of action data on it’s antineoplaston A10 and antineoplaston AS2-1 therapy (ANP). These findings were discussed at the 3rd Quadrennial Meeting of the World Federation of Neuro-Oncology in Yokohama, Japan.

In phase II studies, a total of eighty evaluable patients with advanced non-operable brainstem glioma (BSG) have been treated with ANP administered intravenously through an ambulatory infusion pump. Most of the patients (79%) were children, and 63% of all patients failed prior radiation therapy and/or chemotherapy. Due to low performance status, 52 patients were treated under Special Exception. The median duration of treatment was 5 ½ months. ANP was well-tolerated with easy manageable side effects of fatigue, skin rash and electrolyte abnormalities and no chronic toxicities. In the study group, 32% of patients have complete and partial responses, 43% have stable disease and 25% developed progression. Overall survival is 36% at 2 years and 25% at 5 years. These results compared favorably to radiation therapy and chemotherapy (Mandell, et al. 1999, 7% overall survival at 2 years and 0% at 5 years), but should be confirmed in phase III trials scheduled to begin in 2009.

Of these, only the second press release is directly relevant to Billie Bainbridge’s case – the first deals with a similar type of cancer (glioma) but one which affects the optic pathways, not the brainstem. The first press release is, however, indirectly relevant for reasons that will become clear in due course.

So. everything’s going swimmingly at this stage – work on the Phase III trial for brainstem glioma is moving forward fairly rapidly – and September 2009, the Clinic also announced that its had hooked up with the University of Alabama, who provide the bioinformatics for the trial – FDA approval for the trial had been secured and results from phase II had been presented at a prestigious-looking neuro-oncology conference in Japan.

Well, not exactly.

All three of the presentations given at the conference in Yokohama turn out to have been poster presentations (P33, P206 and p241) so that’s ‘presented’ as in ‘stood in front of a poster in a large tradeshow hall’ and ‘discussed’ as ‘answered questions for any passing delegates showed enough interest to ask’, which is not quite the impression one would get if you took the press release at face value.

So, the findings ‘presented’ at this conference do not appear to have been subjected to full peer review, although some preliminary results from Burzynski’s Phase II trial were published in 2003, in a journal called Drugs R&D (current impact factor 1.35, open access since 2010), and in 2006 in ‘Integrated Cancer Therapies), an alt-med journal with a current impact factor of 1.716 (ranked 134 of 185 for oncology journals).

Unfortunately, I don’t have access to Web of Science and so cannot see whether either of these papers has ever been cited by anyone other than one of their own authors.

As for the FDA approval, the full guidance for FDA Special Protocol Assessment can be viewed here (pdf) but in essence what the SPA process provides is not much more than an opportunity for researchers to run their proposed trial protocols past the FDA in order to check that that any results will be admissible if and when a New Drug Application is made, as the FDA’s guidance explains:

In the request for special protocol assessment, the sponsor should pose focused questions concerning specific issues regarding the protocol, protocol design (including proposed size), study conduct, study goals, and/or data analysis for the proposed investigation. Although the questions should be specific to the protocol and should not address overall development strategies, the role of the study in the overall development plan should be clear to the Agency for it to answer the protocol-specific questions.

To facilitate FDA’s assessment of the issues raised by the sponsor, a request in the form of a document separate from the protocol should discuss in reasonable detail all data, assumptions, and information that should be included for an adequate evaluation of the protocol. For example:

• The sponsor should include information to assess the role of the study in the overall development of the drug.

• The sponsor should submit information supporting the proposed trial, including power calculations, the choice of study endpoints, and other critical design features (e.g., choice of control, duration, methods of assessment).

• The sponsor should clearly describe any anticipated regulatory outcomes (e.g., approval of a specific claim, breaking orphan exclusivity, a comparative claim) and proposed labeling that the sponsor believes would be supported by the results of the study.

What the FDA don’t appear to look at in any great detail at this stage is the validity of any evidence relating to the efficacy of the drug to which the trial relates:

Special protocol assessment is designed to evaluate individual protocols primarily in response to specific questions posed by the sponsors. While more general drug development issues (e.g., the number of trials needed or adequacy of supportive evidence for a given efficacy claim) are factors in assessing the overall adequacy of a proposed protocol, they are not considered part of the special protocol assessment program. Questions pertaining to such general drug development issues should be discussed in routine drug development meetings and correspondence with the review or applications division. Such drug development issues should also be discussed with the review office, as appropriate.

Okay, so you can’t just rock up out of the blue and gain approval for a phase III trial. You do have to have done your basic safety work at phase I and have produced some evidence of an effect at phase II but its at phase III where the all the serious testing takes place and tis certain not uncommon for promising looking new drugs to fail at this third stage as a result of either throwing up side effects that weren’t evident at the earlier stages or simply because don’t demonstrate anything like the kind of efficacy that researchers were hoping for.

So, FDA approval means, here, nothing more than the fact that the FDA has accepted that the proposed trial protocol would be suitable for generating supporting evidence for a New Drug Application, if and when one is filed. What it doesn’t mean, however, is that the FDA will maintaining any degree of regular oversight of the conduct of the trial – the Burzynski Research Institute has own Institutional Review Board (i.e. ethic committee), which is supposed to do that, although how effectively it functions is open to question in view of the contents of an FDA Warning letter, dated October 2009, a letter which remains open* more than two years later.

* For warning letters issued after 1 September 2009 the FDA will issue a close out letter when, based on the FDA’s own evaluation, a company has taken firm corrective action to address the failings highlighted in a warning letter.

Worryingly, many of the failures highlighted in the FDA’s warning letter relate to issues in which the FDA have previous identified deficiancies in Dr Burzynski’s work.

In 2001, according to the FDA Clincial Investigation Inspection List, an inspection of Burzynski’s research activities found several problems, including the use of inadequate informed consent form, inadequate drug accountability, a failure to follow investigational plans, inadequate and inaccurate records, unapproved use of a drug before IND submission, i.e. before it had been approved for use in humans, and a failure to report adverse drug reactions. On this occasion, a voluntary 30 day response from Burzynski’s was sufficient to close off this case without further regulatory action by the FDA.

Getting back to Burzynski’s brainstem glioma trial, by September 2009, pretty much everything was looking hot to trot. FDA approval had been secured and the Burzynski Clinic had attracted a couple of credible partners to assist with the management of the trial and the validation of its results – so what happened next?

So far as I can, nothing – as far any further official records, or even press releases from the clinic, go, this particular trial appears to have disappeared into the aether. Burzynski does have a phase III trial listed on the US clinical trials register, this one:

A Randomized Study of Antineoplaston Therapy vs. Temozolomide in Subjects With Recurrent and / or Progressive Optic Pathway Glioma.

This study is not yet open for participant recruitment.

The purpose of this study is to compare progression free survival (PFS), the time from randomization to progressive disease, in children with optic pathway glioma (OPG) age ≥ 6 months to < 18 years, who receive combination antineoplaston therapy (ANP therapy) vs. temozolomide (TMZ); study subjects will have: 1) received prior treatment with carboplatin or cisplatin, which was terminated secondary to toxicity or progression of OPG, or 2) developed recurrence of OPG after completion of carboplatin or cisplatin therapy.

…

Estimated Enrollment: 70

Study Start Date: December 2011

Estimated Study Completion Date: December 2015

Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)

This trial was registered in December 2010, less that two weeks after the timestamp at the Burzynski Clinic’s website shows that its 2009 press release about securing FDA approval for a phase III brainstem glioma trial was added to the site and yet this clearly isn’t that trial – rather this entry relates to the press release issued on 6 May 2009, at which point the clinic reported that its phase II trial for optic pathway glioma had been completed and it would, therefore, go on to seek approval for a phase III trial for this condition, in addition to the brainstem glioma trial that had already been approved.

Curiouser and curiouser, not least as the records for both the phase II trials, for brainstem glioma and optic pathway glioma, are listed as being of unknown status – the record for the brainstem glioma trial at phase II shows that it were last updated in May 2008 and that the trial, which began in August 1998, has no projected end date, while the record for the visual pathway glioma trial at phase II has a start date of June 1996 and a projected end date of December 2011 and was last updated in June 2009, which is a month after the 6 May press releases which announced positive results.

In short, there is nothing whatsoever in the public domain to indicate that the phase III brainstem glioma trial has progressed any further than the two partnership agreements made in 2009 and, therefore, no way of knowing which trial Billie Bainbridge will be enrolled into, if her family can raise the estimated £200,000 needed to secure treatment at the Burzynski clinic. Whether or not this accords with the Bainbridge family’s own understanding of the ‘experimental’ nature of the treatment offered by the Burzynski Clinic is anyone’s guess but, looking at this from the outside, it seems to me to be a most unsatisfactory state of affairs, particular if – as seems entirely possible – would be patients are being attacted to clinic by its press release and the implicit promise of a slot in a well regulated phase III trial.

In all this, significant questions remain about the actual nature of the treatments that are being administered by the Burzynski Clinic, questions which David Gorski explores in some considerable detail over at Science-Based Medicine. The focus of this particular article is not the claims that Burzynski has been making for his ‘antineoplaston therapy’ but rather the evidence that’s accumulating about his use of conventional cancer meds:

Although antineoplastons are the dubious cancer therapy upon which Dr. Burzynski built his fame, they aren’t the only thing he does. Despite the promotion of the Burzynski Clinic as using “nontoxic” therapies that “aren’t chemotherapy” by “natural medicine” cranks such as Joe Mercola and Mike Adams, Dr. Burzynski’s dirty little secrets, at least as far as the “alternative medicine” crowd goes, are that (1) despite all of the attempts of Dr. Burzynski and supporters to portray them otherwise antineoplastons are chemotherapy and (2) Dr. Burzynski uses a lot of conventional chemotherapy. In fact, from my perspective, it appears to me as though over the last few years Dr. Burzynski has pivoted. No longer are antineoplastons the center of attention at his clinic. Rather, these days, he appears to be selling something that he calls “personalized gene-targeted cancer therapy.” In fact, it’s right there in the first bullet point on his clinic’s webpage, underlined, even! Antineoplastons aren’t even listed until the third bullet point.

To the growing list of conventional meds which appear to be in use at the Burzynski Clinic I can add another, courtesy of a series of FDA import refusal reports dated 3 Dec 2010 is which Dr Stanislaw Burzynski is listed as the manufacturer of a number of items of medical equipment and drugs which were picked up in transit, from overseas, by the FDA’s Florida division. The list of items includes Burzynski’s own ‘Antineoplaston A10‘ together with what looks to be all the equipment necessary to construct a delivery mechanism (Sigma pump, connectors, spike set, etc.) and a batch of Heparin, an anti-coagulant common used to counteract the risk of venous thromboembolism in cancer patients but also a drug which has been investigated as a potential anti-tumour agent on the back of animal studies which indicated that the drug may inhibit metastasis in some cancers.

These reports do not, unfortunately, identify the would-be importer, but nevertheless it would appear that someone in the Florida area did attempt to import what appears to be a DIY antineoplaston therapy kit from a non-US supplier, albeit that one of the components, (antineoplaston AS2-1) appears to have missing from the inventory, all of which is just a little perplexing.

Returning, finally, to The Observer, Andy Lewis makes note of an important conflict of interest in the paper’s coverage of this story:

First of all, and let’s get this out of the way, as Pritchard himself admits, he has a conflict of interest. His son plays in the band Everything Everything which held a benefit gig to raise money to send a sick child to the Burzynski clinic. The original article was written by the Uncle, Luke Bainbridge, of the poorly four year old who also happened to have been the Music editor for the Observer. This involvement with such an emotive issue should have required more dispassionate voices at the paper to respond.

One cannot really fault The Observer for its desire to offer a helping hand to someone associated with the newspaper but, as both Gimpy and Dr Aust note in comments, this understandable desire cannot reasonably be acted on by a newspaper if it comes at the expense of the paper’s own journalistic standards. There is far more to be concerned with here than just the experimental and unproven nature of Burzynski’s ‘antineoplaston therapy’ or the crippling costs of enrolment in Bruzynski’s trials. Much of the research and commentary provided by bloggers over the last week has focussed, quite rightly, on the uncertainties surrounding the exact nature of the treatments provided by the clinic and on the various allegations and evidence of unethical practices at the clinic; of failures to obtain informed consent prior to treatment or disclose, fully, the nature of the treatment being given to specific patients, the alleged failure of the clinic to inform one patient that the treatment they were being given simply wasn’t having any effect at all, despite this being confirmed by three MRI scans over the course of an eleven month period.

These are anything but trivial matters or mere side issues and they are certainly not concerns that I, or any other blogger could reasonably overlook, in all good conscience, in the name of not upsetting the patient/family by depriving them of what looks for all the world to be nothing more than a false hope. I’m not going to criticise any parent for resorting to desperate measures in a desperate situation but that does not, of itself, justify anyone turning a blind eye to any of these concerns, least of all a broadsheet newspaper with a proud history of high quality, investigative journalism.

For more perceptive commentary of this story and The Observer’s response, can I recommend Keir Liddle’s article ‘Burzynski: A Perfect Storm?” and if you really want to help then bunging a few quid in the direction of any the following charities is always well worth a punt:

Cancer Research UK

Childhood cancer: searching for the genes behind the disease, Cancer Research UK

Macmillan Cancer Support

CLICSargent

Marie Curie Cancer Care

You could also take a few minutes to look up your nearest hospice or palliative care service and offer them a bit of much needed support – Help for Hospices has a searchable database covering the UK and Ireland which appears to include both NHS palliative care services and charitable service providers. Although the hospice movement does receive some NHS funding, what they do receive is nowhere near enough – the underfunding of the Hospice movement is, sadly, one of our longest running and least well known national scandals – and pretty much all charitable hospice rely heavily on donations, income from charity shops and, in some cases local lotteries*, in order to maintain their much needed services.

* It should go without saying, but if your local hospice does run its own lottery then play that rather than Richard Desmond’s ‘Health Lottery’ – the prizes might not be as good, but much, much more of your money is guaranteed to go directly to support your local hospice.

And finally, I’d just like to put in a good word for Cruse Bereavement Care and remind everyone that if you are making a donation to a UK registered charity and you’re a UK taxpayer then, before you part with your cash, please do find out whether you can donate via HMRC’s Gift Aid scheme – it’s the one tax avoidance scheme that you can feel good about using, even in these difficult times.