In 2008 Allmedic Pty. Ltd. approached Dr. Anthony Dixon to lead an industry initiated trial of their photodynamic therapy (PDT) product, - Tru PDT. A trial of this type requires that all costs associated with the trial are met by the sponsoring company.
Dr. Dixon agreed to lead this trial. As part of the consideration for his involvement, Allmedic distributed shares to family interests of Dr. Dixon.
As a consequence, Dr. Dixon declares he had and has a conflict of interest in a positive outcome for this PDT trial and the Allmedic company.
Dr. Dixon took many steps to manage this conflict.
1. Dr. Dixon undertook to ensure that any profit or remuneration resulting from this shareholding would not be retained by the Dixon family but would be donated to charity for the purposes of further medical research.
2. Independent doctors were involved in the monitoring of the follow up of Dr. Dixon’s patients that were enrolled in the trial. These doctors had no interests or otherwise in the success of this PDT product or Allmedic Pty. Ltd. This step best ensured objectivity in assessing patient outcomes.
3. Dr. Dixon handed responsibility of these shares to a third party to manage. Any decision regarding these shares, including purchase or sale of the shares will only be made with such separation. Correspondence regarding the shareholding would be forwarded to the independent manager for consideration. This includes communications from Allmedic.
4. Dr. Dixon engaged a solicitor to oversee the management of these Allmedic shares and to advise the manager of these shares when and where requested.
5. Dr. Dixon declared this interest to the ethics committee overseeing the trial and to the co-investigators.
6. Dr. Dixon undertook to ensure that his education of this ALA product would include information such as adverse outcomes experienced and patient dissatisfaction, - if any.
In 2009 the trial was closed early following numerous issues including safety issues. Some patients suffered severe and prolonged adverse outcomes, - well in excess of the range of adverse outcomes suggested by Allmedic. Indeed permanent face scarring has occurred.
Since these adverse outcomes became apparent, Dr. Dixon has:
1. Reported such adverse events to the ethics committee overseeing the trial as well as to the Therapeutic Goods Administration.
2. Ceased any further usage of this PDT.
3. Offered refunds to patients that were previously treated with this PDT outside of the trial.
4. Apologized to all patients managed with this PDT either within the context of the trial or otherwise, explaining that “Had we known at the time that which we know now, we would never have suggested you be managed with this PDT”.
5. Continued to closely monitor all patients managed with this PDT at the Skincanceronly practice.
6. Educated doctors regarding these adverse events in Dr. Dixon’s education program
In this way Skincanceronly believes that conflict of interest issues have been addressed as carefully and fully as possible.
A further issue arose in late May / early June 2010. Dr. Dixon was one of three Censors of the Australasian College of Skin Cancer Medicine at that time.
An article was published in the College ejournal incorrectly suggesting that an ALA was FDA approved. There was only one FDA approved ALA and that product was not being used in this case study. The Censors deemed that this needed to be corrected.
Ordinarily a Censor will withdraw himself when he perceives he has a conflict of interest in a Censorial matter. But for me to withdraw myself at this point would mean to withdraw from providing information about the patients that had suffered prolonged and severe adverse events. No other College official had confirmed these adverse events.
It was important at this time for someone else in the College to interview / examine these patients so as I could then withdraw my Censorial involvement in this matter. Several patients agreed to be interviewed and examined by the College President or his representative. I wrote to the College President asking him to assess these patients or advise of a doctor who could do so on behalf of College. The President declined to interview or examine the patients or to appoint a doctor to examine these patients on his behalf.
As such, I was left in the invidious position of needing to continue in this Censorial capacity on this issue. The alternative of withdrawing from the matter would amount to the potential conflict of failing to provide input on the safety concerns.
The Censors later provided and published the following correction:
Australasian College of Skin Cancer Medicine wishes to apologise for an error in the final component in the May ejournal case study. We refer to the following paragraph:
“Patients with severe facial actinic damage but no obvious tumours are offered full facial PDT (as indicated by the American FDA . . .”
ALA is by nature an intrinsically unstable substance. Indeed this is essential to its mechanism of action as it is designed to react to light. Having it stable at the time and site of administration has been difficult to achieve.
Indeed there is only one ALA product that has been approved by the United States Food and Drug Administration (FDA). This is the DUSA ALA product called Levulan© that comes in a delivery system known as a Kerastick©. DUSA do not have Australian Therapeutic Goods Administration (TGA) approval for their Levulan and do not market or sell the product here. Details of Levulan can be found at the DUSA web site;
http://www.dusapharma.com/levulan-photodynamic-therapy.html
This Levulan product was not being used in the case study and as such this statement should have read, “as NOT indicated by American FDA”.
The Kerastick has been demonstrated to deliver ALA to the skin in a stable and reliable form that has been shown to have a predictable effect on the skin. Other simpler ALA delivery systems have not been demonstrated by independent research processes to replicate this Kerastick reliability.
There has been concern in Australia regarding a number of simple ALA products that have been marketed under such names as “Allmedic Tru PDT”, “Photodynamix Therapy” and “ACP – 5 ALA”.
The lack of knowledge of the safety and efficacy of these products has resulted in them being demarcated as unacceptable by College. Details of which products are recommended by ACSCM for management of skin cancer and actinic damage can be found on the College’s traffic light sheet.
Prolonged and severe adverse events have been reported following usage of Allmedic Tru PDT and these events are currently subject to an investigation by the TGA here in Australia.
There is no independent peer reviewed and published studies that support usage of the various ALA products sold in Australia. There is no basis to suggest that they can be regarded as bioequivalent to Levulan.
We wish to apologise to DUSA for suggesting that other products might have the same level of evidence of efficacy and safety and formal approval that they alone have demonstrated and achieved.
- Censorial input from ACSCM
- July 2010
Clinical Censor Dr. Lloyd Cleaver endorsed the correction.
Dr. Cleaver wrote the following to the College President:
The practice of using a non FDA approved drug based is contrary to the rules and regulation of the FDA and good practice. The use of non FDA approved 5 ALA have lead to serious side effects and have not had the scientific scrutiny of phase II and III research data.
The DUSA Levulan product is impeccable as it is dispensed in an unbreakable vial which provides accurate dosage. Other preparations may have problems with stability and could yield potentially bad results. There are multiple lawsuits involving the use of non-FDA approved ALA resulting in damage when non Dusa formularies are used. This is partly because Dusa owns the patent to its formulary. Please see the attached articles regarding this.
It is inappropriate for any college members to support the use of a medicine which is not approved and could be a potential detriment to individual patients.
Lloyd Cleaver DO
Very soon after this correction was published on the College web site it was withdrawn, - apparently by the College Executive Officer. I feel that I have made every reasonable attempt to disclose these adverse events and in doing so not be in a situation where I was aware of safety issues and was not disclosing them through a conflict.
However, the College President later claimed that the allegation of burning and scarring cannot be supported. This is a very difficult position for him to take after having declined the opportunity to confirm or refute the adverse events himself.
The Censors also considered that the dilemma might have been avoided if the journal was peer reviewed. The Censors were also advised confidentially by some College Board members that some members of the Board had a potential conflict of interest in this issue in that they were selling / profiting from this ALA treatment. We were advised that some Board members with such conflict may be continuing to participate in the discussion and were arguing against the Censor suggested correction.
Dr. Cleaver wrote the following to the College President:
Anthony and I have discussed several issues, including the PDT question.
I am pleased with the E - journal correction and the brand verses generic guidelines.
Regarding the censors acting as the editor for the E - journal, this should only be for a short period of time until a peer review process can be put in place. Once the peer review process is in place then the censors should act to monitor the peer review process. This would be done with guidelines. There should be a conflict of interest statement developed. This statement should be signed by board members, peer reviewers, authors, and censors. If there is a conflict or perceived conflict of interest, the individual should not be involved with the issue. This should be signed and renewed annually.
The ideal censorial process involves a careful separation between Censor panel and Board representation.
The Board should respect and implement considered censorial direction once the Board appoints its Censors.
When questions arise regarding the censors, Anthony can act as a chair for the censors until he can relay the information to Robert and me in a timely manner.
The brand versus generic guideline referred to and developed by the Censors was as follows:
Usage of generic versus brand names in ACSCM education
In general all Australasian College of Skin Cancer Medicine (ACSCM) education that involves discussion of pharmaceutical products should refer only to the generic names of the products. Agents such as lignocaine, dicloxacillin, paracetamol, adrenaline, cephalexin, aspirin, chloramphenicol, warfarin and erythromycin should be referred to only in generic form. There are many other examples.
When a generic drug name is mentioned in ACSCM education, the understanding will be that the specific agent being used is a relevant authority approved** version of the drug.
EXCEPTIONS
There are circumstances where usage of brand names is preferable and other times when usage of brand names is needed in quality and accurate education. This guideline serves to provide assistance to ACSCM members regarding circumstances when drug company brand names can or should be used.
1) Multiple agents:
At times a product is a combination of numerous active ingredients. An example is sunscreens. At times the individual ingredients are not widely recognized and understood. The formulation base also often varies from brand to brand. As such, describing multiple agents in a given base is not likely to convey to the audience exactly which product is under discussion. Naming the brand of sunscreen may be the best method of conveying accurate and understandable education. Only approved** sunscreens should be so discussed.
2) Generic not enough
At times the generic drug name is insufficient to identify the product in discussion. An example is topical diclofenac. There are several marketed and approved** versions available. However, most of these products are designed for joint / muscle discomfort and are not designed, tested or intended as an agent to manage actinic keratoses. A different formulation with alternate strength and base has been tested and approved** for actinic keratoses. To provide accurate information to the audience it will be necessary to explain these differences and identify the brand names of the products intended to treat topical actinic damage.
3) Bioequivalence issues
In most cases bioequivalence of two agents is not an issue. However, at times there are differences or concerns and these might need to be addressed in education. An example is botulinum toxin. There are published concerns that some versions by some producers are not the equivalent of others. With this in mind, education might need to identify which specific product was used, and in what strength and quantity, to ensure accurate education is affected. Bioequivalence issues also often arise when there are variations in delivery systems for topical agents.
4) Non approved** agents
Other than approved** therapeutic goods there are many other products marketed and available that may be discussed in the context of skin cancer education. Education should exercise caution when these products are described, especially when other products with the same active ingredient are approved**. It is inappropriate for any college members to support the use of a medicine which is not approved** and could be a potential detriment to individual patients. Whenever such agents are discussed in education, it should be made clear that the product is not approved** and not recommended. If there is an approved** product with the same active ingredient, this product(s) must be distinguished from others and the rigour and process of regulation recognised.
5) Other circumstances
There will be other circumstances when education material might include brand name details rather than only generic names. Whenever this occurs it will be expected that the educator can identify and explain why the generic name was not used alone.
If there is a concern about a specific preparation then it would be irresponsible not to clearly specify the product, generic or otherwise.
** In Australia, the relevant authority is the Therapeutic Goods Administration. In USA the authority is the Food and drug Administration. Other authorities apply in other countries.
Dr. Cleaver’s request that the journal be peer reviewed and that formal conflict of interest statements be prepared was endorsed by me. Indeed the Censors agreed completely with all of Dr. Cleaver’s input. One will note that the ejournal correction was entirely consistent with this generic versus brand policy.
The College also removed the generic versus brand guideline from the College web site as well as the “traffic light” sheet that listed the non approved ALA products.
Anthony Dixon