Allmedic interferes with research on its own PDT

PDT pain greater than surgery pain

We refer to the “JOINT NHMRC/AVCC STATEMENT AND GUIDELINES ON RESEARCH PRACTICE AUSTRALIAN CODE FOR THE RESPONSIBLE CONDUCT OF RESEARCH”, hereinafter referred to as the “code”. NHMRC is National Health and Medical Research Council.

Code Section 7 refers to conflicts of interest. “A conflict of interest exists where there is a divergence between the individual interests of a person and their professional responsibilities such that an independent observer might reasonably conclude that the professional actions of that person are unduly influenced by their own interests.”

Section 7.2 of the code details the requirements of researchers regarding their conflicts. The requirements include that they must “disclose any actual or apparent conflict of interest as soon as it becomes apparent.”

On numerous occasions Drs Smith and Anseline have failed to declare their conflicts whilst listing Griffith as their institution.

1)     Manuscript on pain spray published in 2014

Anseline, W., Grose, D., Smith, P., Murray, S., Messiah, A., Billing, T. (2014). "A plant-derived anti-nociceptive spray for reduction of pain with photodynamic therapy." Photodiagnosis Photodyn Ther 11(4): 467-471.



BACKGROUND: Photodynamic therapy is an effective tool in the management of some forms of skin cancer and generalized solar dermopathy and can be beneficial in the management of acne vulgaris. When used as an area treatment one of the main limiters is the quite severe burning pain that patients feel during the illumination phase of the treatment. OBJECTIVE: To examine the effectiveness of a plant derived anti-nociceptive spray applied prior to and during large area photodynamic therapy. METHODS: A split face or left arm versus right arm, placebo controlled trial was performed on 60 patients to assess the effectiveness of the spray in reducing pain perception. RESULTS: There was a statistically significant reduction in pain at all illumination points during the illumination phase but no significant difference in discomfort levels in the first 72 h post illumination. LIMITATIONS: Only large area photodynamic therapy treatment was performed during the study. No conclusions can be drawn for small area treatments. CONCLUSION: Use of a simple, plant derived anti-nociceptive spray can reduce the discomfort experienced by patients undergoing photodynamic therapy to large areas.



The authors did not disclose that the product being evaluated was one in which they had a financial interest. Dr. Anseline and Smith are directors and shareholders of Allmedic Pty. Ltd., manufacturer of the agent being tested in the study.



The spray tested in the study is advertised on their web site. Drs. Anseline and Smith are listed as directors of the same company.



We have been informed that they failed to disclose this conflict when submitting the manuscript to the journal and subsequently the research was published without the required disclosure.  In this manuscript the authors comment that they obtained “local” ethics approval. They do not disclose the institution. It is not clear whether or not the trial was approved by Griffith, Bond or another recognised institution.

In July 2009 Allmedic published on their web site details of an apparent trial they state they undertook regarding this same plant derived anti-nociceptive spray. A copy of the description of this study on their web site at that time is retained by ACCO.

They claimed at that time that this agent, PDT-Eze had analgesic properties. This is a therapeutic end point and hence would require TGA approval prior to marketing to the Australian public. The TGA would have required evidence of efficacy prior to any approval. At that time we checked with the TGA and there was no approval for any such agent.

The Allmedic web site entry claims a proven reduction in pain scores by approximately 70%. They do not state whether this was a study they undertook to “prove” this point or a study undertaken by others. Either way a literature search repeated in March 2015 fails to find such a study with these outcomes. The web site entry says that the “Allmedic team identified mechanism . . .” suggesting the pain reducing outcomes were findings by their team. They go on to say that, “By reducing nociception with PDT-eze, we have found the post PDT inflammation is also markedly reduced.” This also appears to be suggesting a finding resulting from some form of trial undertaken by them.

This trial must have had animal or human subjects to result in such findings. Such medical experimentation on animals or humans requires approval of a research and ethics committee. We are unsure whether this was obtained prior to the study and the results as they described in July 2009. They do not identify any ethics approval.

The results claimed in their recent manuscript Photodiagnosis Photodyn Ther 2014;11(4): 467-471) are markedly inferior to the results they claimed on their web site in 2009. This raises several important questions. Was the trial data published on their web site in July 2009 approved in advance by a human research and ethics committee? Why have these 2009 results not subsequently been published in a peer reviewed medical journal? Why are the results of the two data sets so different? Was Allmedic in 2009 making false claims about a product by claiming results of a trial that had never been undertaken?    

2)     Letter to the editor of Dermatologic surgery dated December 2014:

Grose, D., Anseline, W., Smith, P. (2014). "Photodynamic therapy for the prevention of skin cancer” 40(12): 1441-1442.

This letter was submitted and published in reply to our research published in the same journal earlier in 2014.



We disclosed in our research that the novel ALA we were testing was marketed and supplied by Allmedic. Our trial had ethics approval from Bond University Human Research Ethics Committee, (BUHREC)

The letter submitted by Drs. Grose, Anseline and Smith fails to declare that they are Directors and shareholders of Allmedic Pty. Ltd., the trial sponsor. Drs Anseline and Smith did list their affiliation as Griffith University.

Their letter repeats false and damaging charges about us that they had formally alleged before. These doctors made a formal complaint containing the same charges to the NHMRC in 2014. We fully cooperated with the subsequent investigation. We made available all trial and clinical records and even the trial patients.

The investigation concluded that none of the Allmedic doctor's allegations could be supported. The Allmedic directors were sent the NHMRC’s detailed report in July 2014. Yet they submitted and allowed publication of their letter containing the same false allegations in December 2014. The report prepared in response to the NHMRC complaint is retained by ACCO.

The Allmedic directors claim that there was a considerable delay before we reported to BUHREC adverse events and that reports were from only one trial site (Author AD). Both claims are patently false and the investigation found this to be the case. Contrary to their claims, the investigation confirmed that there was no delay in reporting adverse events and that adverse events were reported to them from more than one trial site. Geraldton and Townsville trial centres formally submitted adverse events.

We wrote to the  BUHREC Chair of Ethics, Dr. Mark Bahr on July 31, 2009 in which reported adverse events up until that date were summarised for his records. The email documents numerous adverse events at that time and also confirm reports from three centres.

Our manuscript (Dermatol Surg 40(4): 412-419) details the lack of approval of their Allmedic ALA product. This was a shock to us when we discovered this reality after serious patient adverse events were noted during the study. Allmedic had assured us it had achieved all required approval prior to us commencing our study.

In their letter to the editor (Dermatol Surg 40(12): 1441-144) Smith and Anseline explain that it is legal in Australia for a compounding pharmacist to compound a product upon prescription from a medical practitioner. They also correctly point out that the compounded product might be ALA.

While this is true, this has no bearing on the Allmedic ALA which was the product being investigated in our trial.  No prescriptions were involved and the product was supplied directly by Allmedic and not a pharmacy. A photograph of the product being tested in the trial clearly identifies the Allmedic logo. This photo is retained by ACCO along with several of the original research provided ALA bottles supplied to us by Allmedic.

Drs Anseline and Smith further claimed that Allmedic never themselves marketed and sold the PDT agent in question. This is false.  We retain an invoice demonstrating sales of allmedic ALA. This product, during the study and at no stage since has had TGA approval. Our manuscript was correct.

After Allmedic closed the trial we offered the former control patients, who had not received photodynamic therapy, this treatment using the Allmedic-supplied ALA product as per the protocol. This offer on trial closure was a requirement of the approved protocol. We strongly advised them not to have the treatment due to the severe adverse events experienced by some intervention patients.

The trial had governance issues in that the Directors of Allmedic interfered with the independent running of the trial. This continues with their letter to Dermatologic Surgery.

We notified the journal Dermatologic Surgery of the failure of disclosure of conflict of interest regarding the letter (Dermatol Surg 40(12): 1441-1442). In 2015 the journal published a correction.

3)     Interference with our manuscript published in JPRAS.

Drs. Anseline and Smith’s Dermatologic Surgery letter (Dermatol Surg 40(12): 1441-1442) details that they also made a complaint to the Journal of Plastic Reconstructive and Aesthetic Surgery (JPRAS) about our publication of pain data in that journal. Our manuscript was accepted and published on line by JPRAS in March 2013. After receiving their groundless complaint, JPRAS temporarily withdrew the publication to commence an investigation. That manuscript has now been restored and published in the February 2015 edition. It was restored after the editor reviewed the report for NHMRC which determined that Anseline and Smith’s allegations were false and after we confirmed that all the pertinent ethics approvals were obtained. See abstract here

4)     Misrepresentation of false material with intent to deceive

Drs Anseline and Smith made the false claim that other participants and Dr. Dixon chose to cease participation in their 2009 ALA clinical trial. Indeed it was Allmedic who terminated the trial by withdrawing product and support. We retain their letter to Dr Rosengren dated June 15, 2009 that formalises Allmedic’s closure of the trial.  

Drs Anseline and Smith knew their allegations had been found to be false long before they submitted their letter to Dermatologic Surgery in 2014. Yet they proceeded with the publication of these false and damaging claims under the name of Griffith University.

Drs Anseline, Smith and Grose continually attempted to damage the reputations of our research team.  At the same time they have tried to conceal knowledge of the serious adverse events and lack of efficacy of their product from medical colleagues and the public eye. Drs Anseline and Smith have deliberately published demonstrably misleading information about their products for the purposes of misleading the profession and the public. It is disturbing that their personal commercial interests are pursued at the expense of patient wellbeing and safety and medical research ethics.

The false claims they published about our study in Dermatologic Surgery and not declaring their conflicts of interest amounts to knowingly and deliberately falsifying research findings for personal gain. Section 9 and 10 of the NHMRC code define further research misconduct and examples of research misconduct, stating: “Misrepresentation: A researcher or reviewer shall not with intent to deceive, or in reckless disregard for the truth: state or present a material or significant falsehood”.

The list of misrepresentations and falsehoods by Drs Smith and Anseline includes their claims of:

  1. An ethics embargo on the data
  2. Delay in reporting adverse events
  3. Trial closure by either me or our research team
  4. Allmedic never marketing or selling ALA
  5. False reporting of adverse events (even though these events had been subject to independent confirmation)
  6. No other trial site reporting adverse events
  7. Formal approval of the ALA study product
  8. Our continuing with a trial inappropriately subsequent to ethics closure of the protocol
  9. The ALA PDT being only provided by a pharmacy following prescription
  10. PDT Eze reducing pain scores by approximately 70%

Their misrepresentation of their products continued for more than five years to and including their letter in December, 2014." Dermatol Surg 40(12): 1441-1442.

This timeline and persistence meets the NHMRC code’s section 10 requirement that research misconduct needs “intent and deliberation, recklessness or gross and persistent negligence”.

   


Section 10 also highlights false information regarding adverse events on research subjects as being an example of research misconduct. This raises a further uncertainty. When Anseline and Smith obtained “local” ethics approval for their study (Anseline, W., Grose, D., Smith, P., Murray, S., Messiah, A., Billing, T. (2014). "A plant-derived anti-nociceptive spray for reduction of pain with photodynamic therapy." Photodiagnosis Photodyn Ther 11(4): 467-471.), did they notify their “local” research and ethics committee about the adverse events found in our trial in 2009? If this local ethics approval had been obtained after July 2009 then full disclosure to the ethics committee would have required inclusion of such details.

To fail in such disclosure would be a further incident of research misconduct as per section 10 of the code. It is also noteworthy that whilst Anseline and Smith have repeatedly denied that our trial patients suffered severe post procedural pain, their PDT-eze trial was to investigate a product to reduce post procedural pain. This, in itself, confirms their knowledge of a post procedural pain problem with their PDT. Note that post procedural pain is pain following illumination. It is accepted that PDT can be painful during illumination, including when using the regulated FDA approved Levulan® version.

Section 10b of the NHMRC code lists examples of research misconduct such as:

  • Misrepresentation of results
  • Failure to declare and manage serious conflicts of interest
  • Risking the safety of human participants

Anseline and Smith have perpetrated all of these.

Section 10b also advises that a lack of ethics approval for human research constitutes research misconduct. We are unclear as to whether Anseline and Smith’s research regarding PDT-Eze has satisfied this full requirement at all times.

Dr. Anthony Dixon

This report has been provided subsequent to endorsement by my co-investigators, Professor John Dixon, Dr. Howard Steinman, Mrs. Mary Dixon and Dr. Stuart Anderson