An anonymous contactable complainant, who described himself/herself as a doctor, complained about email invitations from a third party about prostate-specific membrane antigen (PSMA) targeted therapy for the treatment of prostate cancer patients.
The complainant received three emails in April 2021 about a continuing professional development (CPD) activity called ‘understanding novel therapeutic options for metastatic castration resistant prostate cancer' and stated that it was a tad excessive to get invited to the same module three times in 12 days.
The complainant stated that this activity was supported by Advanced Accelerator Applications (AAA), a Novartis company and was intended for an international, non-US audience. The company pushed the invitation to a UK health professional distribution list and even had CPD accreditation from a UK College to make it more attractive. The activity made a few claims about the therapy, including how it compared to chemotherapy.
The complainant referred to one slide stating that it was a new agent which benefited patients with advanced prostate cancer and could be given safely before cabazitaxel. However, what was omitted was that this treatment could not be prescribed in the UK yet. Efficacy and safety claims were made about a treatment that was claimed to be new but in fact was unlicensed in the UK or anywhere in the world.
The complainant stated that it was brave to say some novel (read unlicensed and unproven) treatment was safe, instead of a licensed treatment that had been around for years. The presenters boldly endorsed this unlicensed treatment for clinical practice suggested combining it with other treatments. The complainant could find no study which had ever investigated such a combination.
Another slide discussed a patient who had 10 cycles of treatment, deteriorated, and subsequently died but allegedly had an improved quality of life while his bone marrow failed. The complainant stated that claiming anecdotally that the patient said he felt better while his bone marrow failed and he died, was a suspect medical statement to make. He also appeared to have been overtreated. All protocols suggested six cycles of treatment and this patient received 10 cycles.
The complainant stated that it was statements like these, under the sponsorship of a pharmaceutical company, which made him/her and other clinicians suspicious about the promotional practices of pharmaceutical companies.
The complainant shared another CPD activity on the same treatment: exploring systemic therapies in mCRPC: targeting PSMA to improve patient outcomes..
The complainant concluded that firstly, a pharmaceutical company was paying to generate a series of CPD activities on a ‘novel treatment’ for prostate cancer. The company declared sponsorship as an unrestricted educational grant. The company must have reviewed the slides and seen the wild claims and allowed them to be made.
Secondly, the complainant stated that he/she was registered with the third party as a doctor based in the UK and the programme was clearly planned to target UK doctors.
The complainant alleged that neither of the two speakers declared any financial involvement with Advanced Accelerator Applications or Novartis. One of the speakers was an investigator in a named study where he/she disclosed working as a speaker and advisory board member for Novartis. The complainant stated that surely this was important information to know when listening to his/her opinion on this compound and queried why was this not disclosed.
The complainant stated that Novartis planned to licence the treatment discussed in this CPD activity and that it was ‘a bit naughty’ to keep the disclosure so vague that it was not immediately apparent that the company that intended to profit from selling this treatment was the one that sponsored this activity. That disclosure was subtly yet grossly misleading by omission.
In addition, it was nearly impossible to believe that neither of these two experts had received any further payment from the Novartis family of companies.
The detailed response from Novartis was given below.
The Panel noted AAA’s submission that a Master Funding Agreement was signed in November 2020 between its global medical affairs department, based in Switzerland, and the third party.
The Panel noted that it was a well-established principle under the Code that UK companies were responsible for the acts or omissions of overseas parents or affiliates that came within the scope of the Code. The videos in question were available for UK health professionals as well as others in Europe and the rest of the world (not the US). ‘Understanding novel therapeutic options for metastatic castration-resistant Prostate Cancer’ material had UK accreditation for CPD by the Faculty of Pharmaceutical Medicine (FPM). The Panel considered that the arrangements came within the scope of the UK Code.
The Panel noted AAA’s submission that the agreement provided that the third party would develop independent medical educational activities following a request for funding from AAA for a specific educational activity and AAA’s explanation of the process for submission and review of a funding request.
The Panel noted that it was possible for a company to sponsor material produced by an independent organisation which mentioned its own products and not be liable under the Code for its contents, but only if, inter alia, there has been a strictly arm’s length arrangement between the parties. In practical terms the arrangements must be such that there can be no possibility that the pharmaceutical company had been able to exert any influence or control over the final content of the material.
The Panel noted that the first activity ‘Understanding novel therapeutic options for metastatic castration-resistant Prostate Cancer’ consisted of two health professionals discussing case studies and deciding on the best treatment options to suggest for each patient.
In the first case study, the first speaker stated that he/she would certainly consider the patient for lutetium PSMA-617 and that he would have been eligible to participate in the TheraP and VISION trials, provided he met other eligibility for these trials. However, following further discussions of the trials, it was determined that the patient was not suitable for lutetium PSMA-617.
In the second case study, the patient was referred for the TheraP trial (a randomised phase 2 study comparing lutetium PSMA-617 to cabazitaxel). Whilst the second speaker stated that if the patient was not able to join a clinical trial, he/she would probably advise cabazitaxel treatment. The first speaker stated that the man had a very good response to docetaxel which might be another reason to try cabazitaxel but considered lutetium PSMA as another option. He/she further stated that
‘when we embarked on the TheraP trial, we had uncertainty on how lutetium would compare to cabazitaxel. Now we have the results of that trial published in The Lancet. I think it's certainly a good treatment option if it's available. However, it's not yet available in most parts of the world, so cabazitaxel is certainly a good option’.
The second speaker further stated
‘I look at the course of treatment in this man, both cabazitaxel and lutetium PSMA have been effective. The durability, perhaps of both, a little disappointing, but when we combine them, he's done well. I think this is a message with lutetium PSMA-617 that it's not an alternative to cabazitaxel, but a new treatment option and we can sequence it either before or after. Here we can see that cabazitaxel can be delivered safely after lutetium PSMA-617, that's certainly my clinical experience. This is a good treatment option and you can use it the other way as well, lutetium is quite easy to deliver after cabazitaxel’.
In the third case study, the first speaker suggested the patient would have been a suitable candidate for the VISION trial; he had already had cabazitaxel so he would not have been a candidate for the TheraP trial. It was explained that the patient’s PSA became undetectable after the third dose of lutetium PSMA-617 which was described as being remarkable particularly after not being able to achieve undetectable PSA after prior lines of therapy including 4 lines of systemic therapy, docetaxel, abiraterone, enzalutamide, and cabazitaxel. The speaker pointed out that this was not typical and was not seen very often with lutetium PSMA-617, perhaps only in 5% of cases but it was rather spectacular when it was. The patient was described as having had a total of 10 cycles of lutetium PSMA-617 but after the last treatment, his PSA rose sharply again and he eventually developed a pancytopenia and PSMA-PET scan showed diffuse marrow infiltration and he died at around 55 months; it was noted that his quality of life was exceptionally good; his pain improved after the very first dose of lutetium. It was described as a very impressive case, where the patient received great benefit for a long time.
The second speaker stated
‘Now we have PSMA-targeting agents with PSMA lutetium being the most developed agent in parallel to bites and actinium-based drugs. We're waiting for the readouts of the VISION trial, which is the very 1st phase 3 trial for PSMA lutetium, but we are quite confident that the randomized phase 2 trial conducted in Australia, will continue to show efficacy with cabazitaxel as a comparator.’
The first speaker’s summary was that lutetium PSMA-617 was a new class of therapy. The phase 2 data were fairly convincing, and they had quite a lot of clinical experience with it as well, but it was an additional option. It did not replace existing options or current options which were still on the table. He further stated
‘Hopefully the results of the VISION trial will make this therapy widely available and FDA-approved with all the global consequences of that. When that happens, I think the situation will move to one of deciding when to best sequence lutetium therapy amongst all these other treatment options, and that will need multidisciplinary discussion’.
The Panel noted AAA’s submission that prostate-specific membrane antigen (PSMA) was the protein linked to prostate cancer and targeting these proteins with a standardised therapy was a new approach; there were currently 36 PSMA targeting compounds in development other than PSMA-617, 7 of which were owned by AAA (including PSMA-617). The Panel noted, however, that the activity appeared to focus on PSMA-617 and included what in the Panel’s view were promotional claims for the unlicensed medicine.
The Panel noted that the email sent by the third party to AAA with the funding request attached stated:
‘I am pleased to attach an Independent Medical Education Grant proposal in the PDF doc. for your consideration together with a line item budget spreadsheet in excel doc. The proposal contains some cost efficiencies we applied in order to keep within the budget stated. We did need to also remove the Podcasts to come in line with budget, however, if you did want them added we could always discuss pricing options.
I hope you like the proposal and it is in line with your expectations and as always please reach out to discuss any aspect as you feel appropriate…’
The Panel noted AAA’s submission that the first activity, titled ‘Understanding Novel Therapeutic Options For Metastatic Castration-Resistant Prostate Cancer’, was aimed at oncologists, urologists, radiologists, pathologists, and other clinicians involved in managing patients with metastatic castration-resistant prostate cancer (mCRPC). The Panel noted that the funding request proposal listed the learning objectives for the activity as being increased knowledge regarding the latest clinical data for emerging treatment modalities for mCRPC and greater competence related to treat patients with mCRPC based on disease-specific characteristics. The funding request proposal included that the content would include focus on, inter alia, current approaches with Checkpoint-blockade immunotherapy, PARP inhibitors and PSMA targeted therapies including PSMA-Radioligands; PSMA-targeted CAR-T therapy, and PSMA-targeted Bi-specific T-cell engagers (BiTEs). The Panel noted that according to the second speaker, it appeared that PSMA lutetium was the most developed PSMA-targeting agent in parallel to bites and actinium-based medicines.
The Panel noted that it appeared from the email from the third party and the funding request that AAA would have had a clear idea of what would be covered before deciding whether or not to fund the request; the Panel considered that AAA could exercise its discretion to elect an activity and queried whether the arrangements with the third party were truly arm’s length. It appeared from the proposal that the project would only go ahead with AAA’s support and that it had some influence over the project, for example, whether to include podcasts or not, or if the proposal was ‘in line with expectations’. The Panel thus considered that there was no strictly arm’s length arrangement and in that regard the company was responsible under the Code for the content. The Proposal at a Glance referred to minimum audience guarantees and that copies of the slides and transcripts would be made available. The payment was referred to as a grant to develop the initiative.
The Panel noted that the activity by the third party was advertised and made available to UK health professionals as well as others in Europe and the rest of the world. In the Panel’s view, it was clear from the funding proposal that the activity would, on the balance of probabilities, include discussions about AAA’s pipeline products, 68Ga-PSMA-11 and 177Lu-PSMA-617, which were not yet licensed. The Panel queried whether it would ever be acceptable for a pharmaceutical company to sponsor an activity which it could not do itself.
The Panel further noted that Endocyte, Inc., a US subsidiary of Novartis, had sponsored the clinical studies on 177Lu-PSMA-617 and it was the results of these studies that were discussed in the third party activities. Based on these clinical studies, AAA intended to apply for marketing authorisation for the two compounds. One of the speakers was an experienced clinician in the treatment of prostate cancer with PSMA targeted therapies and had been one of the investigators and the second speaker was also an investigator where the published study disclosed the he/she worked as a speaker and advisory board member for Novartis.
Noting its comments and the content of the first activity above, in the Panel’s view, it promoted AAA’s unlicensed medicine which AAA would be aware of from the proposal and therefore, in funding the project, AAA was responsible for the promotion of an unlicensed medicine and a breach of the Code was ruled.
The Panel noted that AAA reiterated that it had no involvement in the development of the contents of the material and thus did not believe that it could be held responsible for any alleged breach of Clause 7.2. The Panel noted its comments above, that in its view, the activity was not truly an arm’s length arrangement and thus considered that AAA was responsible for the content of the material in relation to its provision to UK health professionals.
The Panel noted the complainant’s allegation that the patient in the third case study had been overtreated with ten cycles of treatment when protocols suggested six cycles and his/her further concern that the presenter claimed an improvement in quality of life (QoL) when the patient’s bone marrow failed and died. The Panel noted AAA’s submission that metastatic prostate cancer was a terminal disease and one of the objectives of treating a patient with this condition was to improve their quality of life and not just survival and whilst most clinical trials treated patients with Lu-PSMA-617 for six cycles there were studies investigating the impact on additional treatment cycles in patients who responded to the treatment.
The Panel noted that according to the transcript provided by AAA, the patient described in the third case study was actually a patient who participated in ‘our’ 1st phase 2 trial, which was a 30-patient trial which was published in Lancet Oncology, a single-arm study back in 2018. The patient received a 68Ga-PSMA-PET scan which showed very intense uptake at all sites of disease and the speaker explained that when a very high uptake on the PSMA-PET scan was seen, as in this case, it was very likely that the patient would respond to lutetium PSMA treatment but the durability of the response was not known. The speaker noted that the patient was treated as part of ‘our’ phase two trial and received 3 doses of lutetium PSMA-617. The speaker explained that the patient who had already progressed after cabazitaxel and had few treatment options left participated in a clinical trial and received the experimental treatment [PSMA-617] and did well. The speaker stated that he/she now had almost 50 months follow-up in this man which was remarkable and he had had a total of 10 cycles of lutetium PSMA-617. After that last treatment, his PSA rose sharply again, the patient eventually developed a pancytopenia and the PSMA-PET scan showed diffuse marrow infiltration and he died at around 55 months. The speaker noted, however, that his quality of life was exceptionally good; his pain improved after that very first dose of lutetium. When the patient came back 24 hours after the treatment, he stated that his pain was already starting to feel better. The Panel noted that Lu-PSMA-617 did not yet have a marketing authorisation and therefore had no proven dosage regimen or proven efficacy. The statements made in this regard, in the Panel’s view, meant that that the medicine had been promoted prior to the grant of its marketing authorisation and the Panel ruled a breach of the Code in relation to each of the complainant’s allegations.
The Panel noted, however, that it was clear that the treatment was given in a clinical trial setting. The Panel did not consider that the complainant had established that referring to 10 cycles of treatment within the clinical trial setting or the effect the treatment appeared to have on the patient’s quality of life within that trial was misleading as alleged and no breach of the Code was ruled in relation to each allegation.
The Panel noted the complainant’s allegation that the activity further suggested combining Lu-PSMA-617 with other treatments but he/she could find no study which had ever investigated such a combination. The Panel, whilst noting its ruling above of a breach of Clause 3.1, in relation to promotion of a medicine prior to the grant of its marketing authorisation, did not consider that the complainant had established that referring to a combination of treatments within the clinical trial setting was in itself misleading as alleged and no breach of the Code was ruled.
With regard to the complainant’s allegation that AAA’s new agent could be given safely before cabazitaxel in patients with advanced prostate cancer, the Panel noted that the transcript, stated ‘Here we could see that cabazitaxel could be delivered safely after lutetium PSMA-617, that's certainly my clinical experience’. In the Panel’s view, the statement related to cabazitaxel, which did not appear to be an AAA nor Novartis affiliated product. The Panel therefore ruled no breach of the Code.
The Panel noted the complainant’s concerns that the two speakers involved in the activities were likely to have been consultants for Novartis, AAA or Endocyte, but that this had not been disclosed.
The Panel noted AAA’s submission that the speakers had no direct involvement for any AAA UK based activities in the past but other AAA affiliates had engaged them as consultants. The Panel further noted that one of the speakers was referred to as an experienced clinician in the treatment of prostate cancer with PSMA targeted therapies and had been an investigator on multiple trials and the second speaker was an investigator in a study published in the NEJM and there he disclosed working as a speaker and advisory board member for Novartis. The Panel considered, therefore, that the disclosure of the speakers’ involvement with AAA and its associated affiliates was particularly important given that the presentations mentioned AAA’s pipeline products and failure to do so was concerning. However, the Panel noted that Clause 23.1 required that contracts included provisions regarding the obligation of the consultant to declare that he/she was a consultant to the company in certain circumstances. The Panel noted that this appeared to be a requirement of the contracts provided by AAA and the speakers were required to disclose all financial relationships with any pharmaceutical, medical device, biologics, or diagnostics company so that the third party might provide this disclosure prior to participation in any such activity. The Panel therefore ruled no breach of the Code.
The Panel noted its comments and rulings of breaches of the Code above and considered that AAA had failed to maintain high standards and a breach of the Code was ruled.
The Panel noted that the complainant provided a list of the three emails with the same heading, ‘Selecting Appropriate mCRPC Patients for PSMA-Targeted Therapy’. Whilst the Panel considered that three emails in the space of twelve days in relation to an activity was likely to be seen as excessive, it noted, from screenshots provided by the complainant and from various documents provided by AAA, that there were two components to the activity. It was not clear from the emails provided by the complainant whether they were promoting the overall activity, the separate parts or a combination of the two. The Panel noted that the Code stated, inter alia, that restraint must be exercised on the volume and frequency of distribution of promotional material distributed. The Panel did not have before it the contents of the emails to determine whether they were promotional and to be sure what exact activity each related to. Based on the evidence before it, the Panel did not consider that the complainant had established that AAA had failed to maintain high standards in this regard and no breach of the Code was ruled.
Clause 2 was a sign of particular censure and reserved for such use. The Panel noted the examples in the supplementary information to this clause included promotion prior to the grant of a marketing authorisation. The Panel noted its rulings above and considered that AAA had brought discredit upon, and reduced confidence in, the pharmaceutical industry and a breach of Clause 2 was ruled.