Compounding

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Per the blog's Current News item Hospital Pharmacy Compounded Rose Bengal 10% for Unresectable Melanoma (December 15, 2015), a New Zealand hospital pharmacist conference included a poster about PV-10 and metastatic melanoma.

According to the American Pharmacists Association, "[t]he inpatient setting of hospital pharmacy is unique in a number of ways. The patients treated by a hospital pharmacist typically have more complicated conditions than those in an ambulatory setting and take multiple medications. A staff pharmacist may have exposure to oncology, intravenous (IV) medication therapy, neonatal care, nutrition, pain therapy, geriatrics, and much more. Staff pharmacists face a varied set of responsibilities including dispensing medication, making purchasing decisions, monitoring drug therapy, preparing IV medication, and overseeing drug administration."

The hospital pharmacist poster of Rose Bengal read (pages 79 [title] and 92 [full abstract]):

Introduction
Intralesional injection with agents that stimulate an immunogenic anti-tumour response, such as Rose Bengal, may be a treatment option for unresectable melanoma [1-3]. A proprietary Rose Bengal 10% formulation (PV-10) is undergoing clinical trials, but the raw material is readily available.  

Case description
The patient was a 70 year old female with unresectable melanoma, who had exhausted all chemotherapy, radiotherapy and surgical options. Palliative intralesional injection with Rose Bengal 10% was proposed to prevent further ulceration and alleviate pain. Efforts to gain clinical trial or compassionate supply access to PV-10 proved unsuccessful. Pharmacy was requested to compound the injection. Staff performed a literature search, and considered legal, ethical, DHB clinical governance and HML compliance implications. Pharmacy then developed a method of compounding the injection, sourced Rose Bengal and prepared the treatment. (Solubility was a particular challenge, as a 10% solution was 100 times the listed solubility of Rose Bengal). The patient was treated with 0.5 ml to 1 ml injected into each target lesion and discharged.  

Discussion
This case illustrates principles that apply to all novel treatments. Legal requirements regarding new medicines, and the Health and Disability Commissioner’s guidance on such treatments must be adhered to. It is important to consider the difference between novel treatments based on recent evidence, and treatments intended in any way to generate further evidence. (The latter being experimental treatments that would require research approval). Compounding such products is a complex operation, and this case required input from medicines information, clinical trials, supply chain and aseptic compounding personnel. Compounding is best performed in an aseptic environment to ensure product quality and operator safety.   

Conclusion
Preparing novel treatments in hospital pharmacies is possible, but complex. Careful consideration of legal and ethical issues is needed, especially for vulnerable patients who have no other treatment options.  

Justification for presentation
We are aware of a further case where a hospital pharmacy has been requested to compound Rose Bengal 10%. The promise of this treatment may lead to other requests. This case also illustrates principles that apply to other novel treatments.  

References
1. Damian DL. Topical Immunotherapy with Diphencyprone for in Transit and Cutaneously Metastatic Melanoma. Journal of Surgical Oncology 2014; 109:308–313
2. Thompson JF. Chemoablation of metastatic melanoma using intralesional Rose Bengal. Melanoma Research 2008; 18:405–411
3. Ross MI. Intralesional Therapy With PV-10 (Rose Bengal) for in-Transit Melanoma. Journal of Surgical Oncology 2014;109:314–319

Takeaways, discussion and questions:

• The abstract/poster appears to speak to the larger topic or issue of compounding a drug product (using sourced active pharmaceutical ingredient) when access to it is desired but unavailable.

"Staff performed a literature search, and considered legal, ethical, DHB clinical governance and HML compliance implications."

• The overarching principle underlying the hospital's decision to permit compounding in this case appears to be strictly patient need.

"This case illustrates principles that apply to all novel treatments. Legal requirements regarding new medicines, and the Health and Disability Commissioner’s guidance on such treatments must be adhered to. It is important to consider the difference between novel treatments based on recent evidence, and treatments intended in any way to generate further evidence. (The latter being experimental treatments that would require research approval)." {Underlined emphasis is mine}

• There neither mention of safety (adverse events) or efficacy, per se. If the medicine caused an adverse event and/or didn't really work, why write a poster in the first place about the topic of having to gin up one's own batch of drug to treat her? It would seem the medical doctor or team treating the patient agreed their was clinical data-based reason to do so.

"Intralesional injection with agents that stimulate an immunogenic anti-tumour response, such as Rose Bengal, may be a treatment option for unresectable melanoma...The patient was a 70 year old female with unresectable melanoma, who had exhausted all chemotherapy, radiotherapy and surgical options. Palliative intralesional injection with Rose Bengal 10% was proposed to prevent further ulceration and alleviate pain."

• Why could the [presumably] New Zealand patient not gain access to an Australian compassionate use program (CUP) site? Did the New Zealand hospital not qualify as a CUP site (did it seek such)? Was the patient to fragile to travel to Australia? Did she not meet the CUP inclusion criteria? Did the medical doctor or team contact Provectus? Nevertheless, he, she or they and their hospital navigated the pertinent legal and ethical issues, and ginned up their own batch of PV-10.

"Efforts to gain clinical trial or compassionate supply access to PV-10 proved unsuccessful....Pharmacy then developed a method of compounding the injection, sourced Rose Bengal and prepared the treatment."

• It was not easy to compound their own PV-10.

"(Solubility was a particular challenge, as a 10% solution was 100 times the listed solubility of Rose Bengal)."

• I don't think the situation described above is a concern to Provectus. Rose Bengal is readily available, such as from Sigma Aldrich. Provectus has several drug substance (Rose Bengal) and drug product (PV-10, PH-10) manufacturers. The company's awarded and allowed patents for this area of intellectual property (IP) fall under Process for the synthesis of 4,5,6,7-tetrachloro-3',6'-dihydroxy-2',4',5',7'-tetraiodo-3H-spiro[isoben- zofuran-1,9'-xanthen]-3-one (rose bengal) and related xanthenes -- awarded as 8,530,675, and allowed as 20140343296 [see Drug substance/product synthesis (December 8, 2015) on the blog's Current News page].

According to Provectus, this IP "covers the process under which pharmaceutical grade Rose Bengal and related xanthenes are produced, reducing the formation of certain previously unknown transhalogenated impurities that currently exist in commercial grade Rose Bengal in uncontrolled amounts. The requirement to identify and control related substances is in accordance with International Conference on Harmonisation (ICH) guidelines for manufacture of API suitable for clinical trial material and commercial pharmaceutical use."

According to management, there is some or potentially notable ability to track Rose Bengal solutions based on the impurities therein (the process of tracking purportedly is covered by the IP). 

Provectus keeps secrets. The make-up of PV-10 also comprises trade secrets.

Also see Underlining (March 26, 2015) on the blog's Archived News III page, from which the below is drawn.

Click to enlarge.

"DMF stands for Drug Master File. I'm curious why Peter inserted this acronym here, and now. A DMF is a submission to the FDA of information, usually concerning the confidential detailed information about Chemistry, Manufacturing and Controls ("CMC") of a drug product or a component of a drug Product. No company must file a DMF, unless information contained in DMF is used to support a new drug application ("NDA")(or an IND or ANDA) and the NDA references the DMF (in which case the Agency would review the DMF). Recent DMFs are a better indicator of intent to manufacture than older DMFs." The point here is that the DMF more than likely contains the trade secret(s), and the company won't hand it/them over until it is acquired.

• Despite not using Provectus' official version of PV-10, did the New Zealand patient benefit from her medical doctor or team's version? There is no evidence one way or the other; however, again, why'd they go to the effort of putting together and presenting the poster?

• The New Zealand situation does not appear to be an isolated one.

"We are aware of a further case where a hospital pharmacy has been requested to compound Rose Bengal 10%. The promise of this treatment may lead to other requests."