1. Ms A, aged 54 years, has refractory[1] multiple myeloma[2] — a type of blood cancer. She was offered a place on a Pfizer[3]-sponsored international drug trial (the trial), which was being overseen by a research trials unit at Health New Zealand │ Te Whatu Ora (Health NZ). The trial was a study to evaluate the efficacy and safety of elranatamab[4] in patients with refractory multiple myeloma. As part of the trial, Ms A was prescribed a broad-spectrum antibiotic, levofloxacin,[5] preventively.
   
   
2. The trial began on 16 October 2023, with the first dose of levofloxacin taken around 23 October 2023. Ms A said that she developed left shoulder pain in mid-November 2023, which initially she considered to be due to injury.[6] However, when Ms A’s right shoulder developed similar pain in February 2024, and this was discussed with her clinicians, a possible connection was made between the shoulder pain and levofloxacin. Ms A was advised to stop using levofloxacin approximately one and a half weeks after this possible connection was made.
   
   
3. Subsequently, Ms A was diagnosed with tendinosis[7] and bilateral[8] adhesive capsulitis[9] (aka frozen shoulder). She believes that levofloxacin was the cause of this and raised concerns about:

1. 1. whether the use of levofloxacin had been appropriate in her case as well as whether, given its risk profile and that it is an unapproved drug[10] in New Zealand, it should have been used in this trial;
      
      
   2. whether she was consented appropriately to the use of levofloxacin; and
      
      
   3. the timeliness of trial staff identifying the possible causality between levofloxacin and her shoulder issues and subsequently advising that she cease using it.

4. At the outset, I note that it is not my role to establish any causation between the use of levofloxacin and Ms A’s shoulder issues. Rather, my role is to assess whether the standard of care provided was appropriate at the time it occurred.
   
   
5. To assist in my assessment of this complaint, I sought a clinical steer from my in-house clinical advisor, vocationally registered general practitioner Dr David Maplesden. His advice is enclosed as Appendix A of this report.
   
   
6. I also sought independent advice from haematologist Dr Nicholas Weber. Dr Weber’s advice is enclosed as Appendix B of this report.
   
   
7. I have relied on the independent clinical advice to assist me in my determination as to whether Ms A’s rights were breached.
   
   

Responses to provisional opinion

8. Health NZ was given the opportunity to respond to my provisional opinion and provided comments and submissions, which I have considered.
   
   
9. Dr B was provided an opportunity to respond to my provisional opinion and had no further comments beyond those already provided.
   
   
10. Ms A was given an opportunity to respond to my provisional opinion and made comments that I have considered.
    
    

Whether the use of levofloxacin was appropriate in this case — no breach

11. Levofloxacin was prescribed to Ms A as a supportive drug as part of the trial, specifically to reduce the risk of sepsis associated with the trial drug, elranatamab.
    
    
12. Ms A told the Health and Disability Commissioner (HDC) that levofloxacin has a well-known adverse event risk profile, particularly regarding musculoskeletal side effects, and that she was at increased risk of tendonitis or tendon rupture from levofloxacin because of her age, activity level, and use of dexamethasone[11] (a corticosteroid) as part of the trial.
    
    
13. Health NZ stated that haematologist Dr B[12] considered whether Ms A had any additional risk factors for complications from levofloxacin before prescribing it to her and concluded that she did not.[13] Further, Health NZ stated that it was necessary for the trial participants to be on preventive antibiotic treatment, and the trial protocols recommended the use of levofloxacin or an equivalent antibiotic of the same class, which was not available in New Zealand.
    
    
14. My advisor Dr Weber advised that the decision to prescribe levofloxacin was in line with the trial protocol recommendation and accepted clinical practice. He commented that fluoroquinolone antibiotics (which include levofloxacin) are in common usage around the world, and notwithstanding that levofloxacin is not registered in New Zealand, its use in the clinical trial was not dangerous or inappropriate. He said that he could see no convincing reason why levofloxacin should have been withheld in Ms A’s case. Accordingly, Dr Weber did not identify any departures from the standard of care in this respect.
    
    
15. I accept Dr Weber’s advice and conclude that the use of levofloxacin in the trial was appropriate. I also conclude that there was an assessment of Ms A’s suitability for levofloxacin and accept that there were no specific risk factors for Ms A that would have warranted the withholding of that medication from her. That said, given that levofloxacin had known risks and that it was not registered for general use in New Zealand, it was important to ensure that an appropriate informed consent process took place regarding its use.
    
    

Consent for levofloxacin — breach (Health NZ)

16. Rights 6 and 7 of the Code of Health and Disability Services Consumers’ Rights (the Code) require that consumers are provided with the information that a reasonable person in that person’s circumstances would expect to receive, including the expected risks, side effects, and benefits of the treating option so they can make an informed choice and give informed consent.
    
    
17. Ms A is concerned that she was not provided with sufficient information about levofloxacin to have consented to its use properly.
    
    
18. Ms A denies being given specific information about levofloxacin and told HDC that the only information she was given about levofloxacin was the information on the pill bottle when it was handed to her on 16 October 2023.[14] She said that she did not receive any information on the possible risks and side effects of levofloxacin. Ms A stated that the first time she was told that levofloxacin might cause significant side effects and might be linked to her shoulder complaint was on 22 February 2024.
    
    
19. Ms A was provided with a copy of the Patient Informed Consent Form (PICF) in respect of the trial on 22 August 2023. She was advised to read it and to ask any questions before signing it.
    
    
20. Ms A had an appointment with Dr B on 5 September 2023 to screen her for eligibility for the trial and to carry out the consenting process. Dr B stated that Ms A was given printed details of the trial protocol, and he discussed the potential risks and benefits of the trial.
    
    
21. The evidence regarding the specific information provided to Ms A about levofloxacin is conflicting.
    
    
22. In its initial response to Ms A’s complaint dated 26 July 2024 (10 months after the consenting discussion), Health NZ stated that levofloxacin ‘as a supportive medication [was] not part of [the] consenting process for the MagnetisMM-5 trial’ and that it did not routinely seek consent for supportive medications. In that respect, Health NZ specifically accepted that it had breached Rights 6 and 7 of the Code (the informed consent provisions). I note that Dr B was identified as having participated in the formal review that led to this response.
    
    
23. In a separate response dated 3 February 2025, after HDC had notified Health NZ formally of an investigation into this matter, and 16 months after the consenting process, Dr B stated that he provided verbal information regarding levofloxacin as a supportive medication. He said that he specifically discussed that joint pain could be a potential side effect of levofloxacin. Ms A signed the PICF at this appointment, and Dr B has stated that she gave verbal consent to the supportive medication.
    
    
24. I note that the PICF signed by Ms A mentions the use of antibiotics preventively but does not explicitly state the drug name or side effect profile, and the trial protocol does not include any information on potential risks associated with levofloxacin. There is no documentation of what verbal information was provided to Ms A regarding potential risks and benefits of levofloxacin, nor is there any documentation of her having given verbal consent. Further, Ms A (in her response to Dr B’s statement) noted that there is a difference between joint pain and tendonitis/tendon rupture, the latter of which is a known side effect of levofloxacin. Ms A (noting that she had been a registered physiotherapist) stated that it is ‘inconceivable’ that she would have consented to taking levofloxacin had she been advised of the risks of tendonitis or tendon rupture, and she refutes being advised of the risks and benefits.
    
    
25. Registered Nurse (RN) C, who was present during the consenting discussion on 5 September 2023, did not identify in her statement (dated 4 February 2025) the content of the discussion but did reference that she provided the levofloxacin to Ms A, informing her that it was an antibiotic to prevent infection, the dosage requirements, and when to commence taking it. No further information was provided at that time.
    
    
26. The Medical Council of New Zealand’s standards on ‘informed consent’[15] and ‘managing patient records’[16] state that providers must maintain clear and accurate patient records of what information was discussed during consenting discussions, including any specific risks that were highlighted, and any consent given.
    
    
27. Moreover, there are heightened obligations when prescribing unapproved medicines. The Medical Council’s ‘Good prescribing practice’ standard that was in place at the time specifically required consent to the risks, adverse effects, costs, or benefits of such medicines (among other things) as well as provision of the information that the medicine being prescribed was unapproved. This is consistent with Medsafe’s guidance on the prescription of unapproved medicines. In addition, my in-house clinical advisor, Dr Maplesden, advised that prescribers have been made aware of the potential risks of fluroquinolone prescribing for some time, particularly regarding connective tissue issues,[17] and such risks should have been discussed with Ms A prior to prescribing.
    
    
28. Health NZ’s ‘Informed Consent’ policy[18] also states that, when verbal consent is obtained, it must be documented in the patient’s clinical record; and, where a consent form is not available, the provider must make clear and accurate notes about the consent process, which may include what information was provided to the patient, when, and by whom.
    
    
29. I am satisfied, based on the standards and clinical guidance given to my investigation, that explicit consent should have been obtained for the use of levofloxacin – particularly noting that it was an unapproved medication – and that this consent should have been documented in the clinical records. That is, the risks and benefits should have been canvassed with Ms A (including the risks of tendinopathy), together with the fact that the medication was unapproved.
    
    
30. Having carefully considered the (at times conflicting) evidence on the content of the consenting conversation on 5 September 2023, I am satisfied on the balance of probabilities that Ms A was not told of the risks of levofloxacin adequately, and, in particular, the risk of tendinopathy. I am also satisfied that she was not told that the medication was unapproved. It is also self-evident from the clinical record that any consenting discussion about supportive medication was not documented.
    
    
31. Having reached these conclusions, I find that Ms A did not have all of the information that she needed to make an informed decision and give informed consent to the use of levofloxacin. In the context where the protocol and PICF did not contain information about the supportive medications, and noting Health NZ’s more proximate response to the complaint that consent to the supportive medications was not sought routinely for the trial, I consider it appropriate to hold Health NZ (rather than Dr B) to account for the breach of Right 6(2)[19] of the Code, and consequently Right 7(1)[20] of the Code — the right to make an informed choice and give informed consent. That is, expectations and a process to obtain consent to supportive medications was absent for the trial, leading to the failure to obtain consent in this situation.
    
    
32. I acknowledge that Dr B and other staff involved in Ms A’s care have since spent time reviewing policies and guidelines and agree that written informed consent should have been obtained from Ms A regarding the use of levofloxacin and that Ms A’s verbal consent should have been recorded. I also acknowledge the further changes Health NZ is in the process of implementing regarding its clinical trial consenting process and use of unapproved medicines. I remind Dr B of the importance of providing sufficient information, especially for unapproved medicines, and accurate clinical documentation that reflects what was discussed with a patient, particularly in situations concerning informed consent and the use of an unapproved medicine.
    
    

Timeliness in identifying possible connection between shoulder symptoms and trial medication, and subsequent ceasing of levofloxacin — no breach

33. Ms A told HDC that she raised concerns about her left shoulder frequently with doctors and nurse coordinators at her fortnightly review appointments, starting in early December 2023.
    
    
34. Health NZ stated that staff took reasonable steps to investigate the cause of Ms A’s shoulder pain and provide support. Health NZ said that Ms A’s left shoulder pain was first reported to trial staff on 25 January 2024 (when it was first documented), and she was advised to stop taking levofloxacin just over a month later, on 5 March 2024.
    
    
35. On 22 February 2024, Dr B identified a possible connection between Ms A’s shoulder pain and either elranatamab or levofloxacin, as Ms A had begun to experience pain in her right shoulder as well. However, Dr B did not advise Ms A to stop taking levofloxacin at this time as he was concerned that this would expose her to a high risk of infection, and he was not sure whether levofloxacin was the cause of the issue.[21] Dr B wanted Ms A to continue on all the trial medications (including supportive medications) until they had an opinion from an orthopaedic consultant. Dr B also planned to discuss this situation with the haematology team.
    
    
36. Following this appointment, Ms A looked into levofloxacin. On or around 4 March 2024, she contacted RN D[22] to ask whether she should cease taking levofloxacin. RN D discussed this with haematologist Dr E,[23] who advised on 5 March 2024 that Ms A should cease taking levofloxacin.
    
    
37. Dr Weber advised that the delay in recognising levofloxacin as a possible cause of Ms A’s shoulder pain was not excessive or inappropriate and that Dr B fulfilled his duty regarding investigation and management of the shoulder pain. However, Dr Weber also advised that the recognition that levofloxacin may have been the cause of the adhesive capsulitis should have prompted cessation of this on 22 February 2024. Dr Weber said that as it was a preventive drug rather than a therapeutic one, it could have been withheld without jeopardising ongoing trial participation, and alternative antibiotic prophylaxis could have been considered. However, Dr Weber also acknowledged that, given the rarity of adhesive capsulitis and the uncertainty regarding its cause in this case, there would likely be considerable variation in opinion among his peers on whether Dr B should have ceased the levofloxacin on 22 February 2024.
    
    
38. I acknowledge Dr Weber’s advice. When evaluating an episode of care in relation to Code rights, I am required to consider what is a ‘reasonable standard of care’, not a gold standard or best practice. In the context of Dr Weber’s opinion that there could be varied clinical responses as to whether or not the levofloxacin should have been stopped on 22 February, I am not satisfied that, in this matter, Dr B departed from a reasonable standard of care. Accordingly, I am not critical that the levofloxacin was not stopped on this date. I also note that Dr B made a considered clinical decision, ensured that there would be further investigation, and recommended appropriate pain relief.
    
    

Changes made and recommendations

39. Health NZ has increased awareness with staff around the potential side effects of levofloxacin, the correct processes for gaining informed consent for prescriptions of unapproved medicines (as per Medsafe guidelines), and the importance of keeping accurate, thorough, and clear clinical notes. Health NZ has also acknowledged that all unapproved medicines need to be accompanied by an information sheet with details on possible side effects. It is updating its procedures accordingly and developing a procedure to include written informed consent for all supportive medications for clinical trials.
    
    
40. I am satisfied that these changes will assist in preventing a recurrence of the issues detailed in this report. I recommend that Health NZ report back to HDC, within three months of the date of this report, with an update on the procedures currently being developed/updated, as stated above.
    
    

Follow-up actions

41. A copy of this report with details identifying the parties removed, except Health NZ and the clinical advisors on this case, will be placed on the Health and Disability Commissioner website, www.hdc.org.nz, for educational purposes.

Morag McDowell

Health and Disability Commissioner

Appendix A: In-house clinical steer to Commissioner

The following in-house clinical steer was obtained from vocationally registered general practitioner, Dr David Maplesden:

‘TO                    :    […]/INV

FROM                :    David Maplesden

CONSUMER      :    Ms [A]

PROVIDER         :    Te Whatu Ora […] ([a research trials unit])

FILE NUMBER   :    C24HDC02377

DATE                 :    4 November 2024

I have reviewed the information on file.

1. I note levofloxacin was being prescribed as a supportive drug (not specifically required as part of the trial or regarded as a trial drug). It is somewhat concerning to read that the provider did not regard such prescribing as requiring patient informed consent, and it is appropriate they have acknowledged this was inconsistent with accepted practice and have changed their processes in this regard. Prescribers have been made aware of the potential risks of fluroquinolone prescribing for some time, particularly in regard to connective tissue issues,^[24] and such risks should have been discussed with the consumer prior to prescribing, as should the ‘off-label’ nature of the prescribing.^[25]

2. Given the main issue in this case is prescribing of levofloxacin (not a trial drug), albeit such prescribing was undertaken to reduce the risk of sepsis associated with the trial drug elranatamab-bcmm, I think it is reasonable to seek external expert advice from a haematologist (preferably tertiary hospital). With the issue of lack of informed consent being acknowledged, expert advice is most likely required regarding the following issues:

• Was prescribing of levofloxacin clinically indicated?
• Were there any contraindications or specific precautions regarding the prescribing of levofloxacin in this case?
• Was there adequate monitoring for potential adverse effects of levofloxacin?
• Was there an appropriate and timely response to Ms [A]’s repeated reporting of potential connective tissue issues (shoulder pain) in relation to the prescribing of levofloxacin?
• Any additional comments?

3. Areas that should probably be outside the scope of expert comment are causation (not possible to make a definitive comment and probably irrelevant in that any suspicion [rather than confirmation] of a fluroquinolone-related adverse event should probably have resulted in prompt review of use of the drug) and ongoing national and international use of the drug (still appropriate to use in selected cases and with appropriate precautions). I note Ms [A]’s reference to compensation, and I wonder if she has investigated lodging an ACC treatment injury claim with respect to her connective tissue issues being a possible unexpected outcome of levofloxacin use.’