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I thought it is good to look from global perspectives to help us understand the strategy Canada took and the current status to deal with the BCG shortage. For the sake of clarity, the term BCG represents BCG for the treatment of non muscle bladder cancer, and the term BCG vaccine is used for the BCG vaccine for preventing tuberculosis. To understand the history of BCG vaccine and BCG for bladder cancer, I recommend everyone to watch the webinar by Dr. Morales which is available on Bladder Cancer Canada site.
Many countries have their own BCG production plants. Most BCG plants started as being managed by the ministry of health of each country, and later some were acquired by private pharmaceutical companies.
Until 2012, when Sanofi run into the contamination problem, Connaught strain BCG which Sanofi Pasteur Canada produced in its Toronto plant had 90% of global BCG market share among those countries who opted to buy BCG rather than producing their own BCG. Tice strain BCG which Merck produced in its NC plant had 10% market share.
The first wave of global BCG shortage
In 2011, the Sanofi’s plant in Toronto was flooded. Subsequently, the company issued a voluntary recall of its BCG vaccine in Canada, Australia and New Zealand. It also halted all distributions of its BCG for bladder cancer to about 50 countries. This was the beginning of the first wave of global BCG shortage. In 2012, Sanofi announced that it would take till the end of 2013 to make the improvements, which were pointed out by FDA after its inspection at the plant.
To alleviate global BCG shortage, Sanofi seemed to have recommended to its customers to use Tice BCG by MERCK. This is because Sanofi and MERCK had a joint business agreement to help each other in the vaccine business. So, most of Sanofi’s customers switched from Connaught BCG to Tice BCG. MERCK started increasing Tice BCG production by 100% to meet the increased demand. But MERCK encountered its own production problem and it created further BCG shortage.
During the first wave of global BCG shortage, countries like the USA, France took an approach to manage the shortage by prioritizing the use of BCG to high risk patients and intravesical chemotherapy. Some countries issued special decree to allow importing other BCGs. I believe Canada’s approach was similar to the US and France and dealt with the shortage without importing other BCGs.
The 2nd wave (current) global BCG shortage
In 2016, Sanofi announced their exit from BCG market. Later Merck announced that they could not meet the demand even though Merck was able to produce nearly 800,000 vials in a year. Countries realized that the BCG shortage of Tice BCG is systemic and could be permanent. This time many countries issued special decree to allow importing different strains of BCG from other countries, mostly BCG Medac (RIVM strain) from Medac Pharmaceutical in Germany. It is interesting to know that Medac imported Onco-BCG from Serum Institute of India temporality to its customers when BCG-Medac became in shortage because of increased demand and upgrading their plan. It is interesting to know Medac recommended 120mg ( 3 x 40mg vial) as full dose which is the standard full dose SII recommends to all of it customers. It is not sure the reason why Health Canada had agreed on 80g (2 x 40mg) of Verity-BCG/SII Onco-BCG to be used as standard full dose.
The US and UK on the other hand decided not to import other BCGs and work within the constraints of reduced availability of Tice BCG. Canada did not utilize special decree to enable Canada to import BCG from other countries, rather issued a temporary license to allow Verity Pharmaceutical to resell Russian strain BCG manufactured by Serum Institute of India and market under the trade name Verity-BCG for NMIBCs which do not involve CIS.
When I look at the outcome of different strategies each country took, surprisingly it seems the US had the most unfavorable results not because their strategies were wrong but because its implementation did not go well. Below is an analysis of the US, UK, France, Italy, Spain, US, UK, Australia, New Zealand, Canada. I will add one by one to this posting.
Hi Joe:
As you know I’m currently receiving Verity BCG. I had heard from you and others before that this variety of BCG is not for patients with CIS which is what I had this time. I did mention this to clinic staff and my uro but have not had a reply to date. I asked the clinic nurse if there was any OncoTice available and maybe I could get switched to that but she told me no Tice is available. The Alberta government imported Verity for patients and that is it.
Question – do you know of any other info/data out there that supports this? I’m concerned that my welfare could be at stake if I’m being given the wrong version of BCG. I would also like to know why this BCG is potentially not suitable for treating CIS. Any ideas on where to find out this info? Many thanks for all the research work that you do. ((((HUGS))))
Hi Marysue,
You raised a very good question. To explain better, I will stop using the word Verity-BCG as it may mislead consumer / Canadian bladder cancer patients that Verity has its own manufacturing facility. I will use SII-BCG (Russian strain) as it is manufactured by Serum Institute of India (SII), which Verity Pharmaceutical exports it and resell it as Verity-BCG. Because except Canada, in every country to whom SII exports SII-BCG is sold under SII-Onco-BCGG, so when other countries are referenced and compared with Canada, the product name will be consistent and will reduce confusion. Please note that SII is a reputable vaccine manufacture. They invested and built a factory to manufacturer Covid-19 vaccine (AstraZeneca) and marketed the vaccine with trade name “Covishield”, which benefited many Canadians early part of the pandemic. So, I think SII is technically competent.
SII-Onco-BCGs are used in several countries, mostly in low income country as the BCG for bladder cancers. In recent years, when Brazil had to shut down their only BCG production fab, Brazil started importing SII Onco-BCG. So I think Brazil is the largest importer of SII-Onco-BCG at this time. Also, it is noted SII-Onco-BCG have been imported temporarily into higher income countries in Europe, i.e. France and Italy by MEDAC, the manufacturer of BCG-MEDAC to supply to its customers when BCG-MEDAC became shortage temporarily. In all cases, SII-Onco-CG are used for HG and CIS. As matter of fact, when BCG was first approved by FDA, it was for CIS.
I will address the rest next. I just wanted to respond in regards to CIS as you are concerned about it.
Joe
Lets talk about Canada’s situation more in detail.
As stated before, countries affected except the US, UK and Canada with BCG shortage, first with Sanofi Connaught BCG, then Merck Tice BCG, decided to import alternative BCG by its government issuing a special decree. This special decree is often called the Special Access Scheme which allows the country importing the drug, which has not been approved officially, to amend the shortage of important drug. A case in point, the paper published in World Journal of Surgery and Surgical Research in Nov, 2019 says “The Therapeutic Goods Administration in Australia granted permission for the importation of an alterative BCG vaccine for treatment of bladder cancer via the Special Access Scheme. Namely BCG-Medac, produced in Germany by Medac. Merck itself have altered the distribution of the Tice-BCG vaccine to ensure fair allocation and prevent stockpiling by allocating stock to countries based on historical demand as well to wholesalers within each country. Most European countries faced with BCG shortage have chosen BCG-Medac though there exists Danish-BCG. which is produced by AJVaccine in Denmark. BCG-Medac is allowed to treat CIS also in those countries. The rationale of choosing BCG-Medac is that already back in 1996, A Dutch group had done a clinical trial comparing Tice-BCG and BCG-MEDAC and reported they were comparable in efficacy and side effects. It turned out that Health Canada has a similar special access program.
Health Canada’s website says Health Canada’s special access programs: Request a drug
If you’re a health care professional, you can request a drug that is not available for sale in Canada through the Special Access Program (SAP). Your request must be for treating a patient with a serious or life-threatening condition where conventional treatments:
have failed or are unsuitable or are not available in Canada
For access to SAP, a health care professional is someone who: is entitled, under the laws of a province or territory, to treat patients with an unapproved prescription drug
practises in that province or territory has prescribing privileges in the respective provinceThe question is why Canada did not use this approach when most countries used this scheme to alleviate BCG shortage problem. Why Canada instead chose to use SII-Onco-BCG, imported by Verity Pharmaceutical – a new startup company ( established in 2016) , even if there have not been any clinical trial which compared SII-Onco-BCG against Tice-BCG? So, Had Canada chosen this approach. This would have been much simpler. We could have been using BCG-Medac from Germany, which had been shown to perform similar to Tice-BCG. I thin I know the reasons, but I leave the explanation to later.
In terms of Verity-BCG not being approved by Health Canada for CIS is some because Health Canada because Verity Pharmaceutical could not present sufficient evidence SII-Onco-BCG would perform comparable to Tice BCG, so I think Health Canada compromised after getting a commitment from Verity Pharmaceutical that they would do the clinical trial in reasonable time frame , and the compromise was to allow Verity to market SII-Onco-BCG under the trade name of Verity-BCG to help alleviate the BCG shortage but restricted the use to non CIS. I do not know the rationale myself why restricted the use to non CIS. Maybe Health Canada wanted to give priority of Tice-BCG with known efficacy to Canadian patients with CIS patients as the high percentage of CIS patients can be cured with BCG.
In terms of CIS, all official documents I have access say Verity-BCG is not approved by Health Canada for CIS. Namely, BCC site, Verity Pharmaceutical site, Health Canada site. I have not seen any changes or update on this matter. It is possible that Health Canada unofficially agreed to allow Verity to market Sii-onco-BCG for CIS because someone told Health Canada that patients with CIS cannot be treated because Tice BCG is not available when it is needed. Anyway, you can access official version of Health Canada limiting Verity-BCG to non CIS.
BCC consensus statement, which is accessible from BCC site, on integrating Tice and Verity-BCG states “VERITY BCG is not approved by Health Canada for the treatment of CIS and its use should be limited to papillary NMIBC (Ta/T1) without evidence of CIS. Specifically: “Verity-BCG is indicated as an adjuvant therapy after transurethral resection (TUR) of a primary or relapsing superficial papillary urothelial cell carcinoma of the bladder stage Ta (grade 2 or 3) or T1 (grade 1, 2, or 3), without concomitant carcinoma in situ. It is only recommended for stage Ta grade 1 papillary tumors, when there is judged to be a high risk (>50%) of tumor recurrence.”
The Verity Pharmaceutical company web site let you access Product Monograph and Patient Information of Verity BCG/ If you click Product Monograph, it will display a PDF file which describes product monograph. In the first page, it says VERITY-BCG has been issued market authorization with conditions, pending the results of trials to verify its clinical benefit. Patients should be advised of the nature of the authorization. For further information for VERITY-BCG please refer to Health Canada’s Notice of Compliance with conditions – drug products
If you click the link, you will reach Health Canada page of drugs which has been issued market authorization with condition. If scroll down, you will find Verity-BCG. It says as follows
Company name: Verity Pharmaceuticals Inc.
Active ingredient: Bacillus Calmette-Guérin (BCG): Strain Russian BCG-I
Date of issuance of NOC/c: December 24, 2020
Related documentationVerity-BCG:Qualification notice which is the link to the document at Health Canada
If you click the link, it reaches to Government of Canada site on Qualifying Notice – Verity-BCG. There it says as follows.
Verity-BCG is indicated as an adjuvant therapy after transurethral resection (TUR) of a primary or relapsing superficial papillary urothelial cell carcinoma of the bladder stage Ta (grade 2 or 3) or T1 (grade 1, 2, or 3), without concomitant carcinoma in situ.
Lets look at how our neighbour – Americans have managed BCG shortage.
The US chose not to utilize their version of Special Access Program to allow importing alternative BCG to deal with the BCG shortage. Instead, The US initiated a clinical trial to compare Tokyo strain BCG by Japan BCG Lab and Tice-BCG enrolling 1,000 patients and see if Tokyo-BCG can be an alternative BCG and if BCG vaccine when it is given before BCG treatment can improves the efficacy of BCG treatment. In addition, all parties who have vested interest in dealing with BCG shortage, i.e. AUA, BCAN, Society of Urologic Oncology, Urology Care Foundation, Urology Trade Association, American Association of Clinical Urologists published a consensus statement in 2019 on the strategy to deal with BCG shortage. The details can be found in the link. “https://www.auanet.org/bcg-shortage-notice”
In summary, the strategy that the US employed was a) Give BCG only for high risk NMIBC, b) Use intravesical chemotherapy for intermediate risk NMIBC, C) Split the dose in ⅓ and share a vial among three patients. D) Recommend early cystectomy for very high risk NMIBC. Note that ⅓ dose was recommended based up a large study in Europe that there were no significant difference in efficacy between patients who had full dose and those who had ⅓ dose.
Also Merck, the manufacturer of TICE-BCG changed their distribution protocol of Tice BCG from order based to quota based. BCG is shipped to distributors of Merck’s vaccine products and let distributors ship Tice-BCG to their customers based upon the past usage pattern.
So what was the outcome of the US strategy?
I think the outcome was much worse than they had expected. In terms of patients, I see occasionally, even in 2023 that patients are posting their anxiety of being notified suddenly that BCG became unavailable, sometimes told to wait, sometimes suggested to switch to intravesical chemotherapy, or just by being told to receive ⅓ dose due to the BCG shortage. I think sporadic shortages may be caused also by ineffective quota based BCG distribution protocol.
The ⅓ dose was difficult to implement, especially in community hospitals. Because a vial of BCG must be used within 2 hours after opening, the hospital has to have three patients come to the hospital within the time frame. Also, in the US, hospitals or urologists have to request payment from the insurance company for which patients are covered. The problem was that there was no code they could charge for ⅓ dose. It took for a while before insurance company came up with 1 mg as a unit. So, ⅓ dose can be expressed as 1mg x 17 each to express 17mg, which is ⅓ of Tice-BCG 50 mg vial.
Also, community hospitals are very familiar with BCG treatment protocol but not so much on intravesical chemotherapy. So, 56% of hospitals used BCG for intermediate risk in spite of the consensus statement, which stated that intermediate risk should be treated with intravesical chemotherapy. In the end, hospitals and urologists were quite unhappy with BCG shortage causes and requested the development of non-BCG based therapies as high priority for BCG naïve patients.
When I consider what if Canada followed the strategy which The US employed, probably we would have experienced similar problems. So, I think Canada’s strategy to treat patients with full dose, and importing alternative strain BCG was a good strategy. It would have been better if Canada used the Special Access Program and imported BCG with strain which had been shown to have comparable efficacy and side effects with Tice-BCG like European countries had applied.
Let’s look at how European countries dealt with BCG Shortage.
The United Kingdom
The UK with the population of 67 million compared to 38 million in Canada estimated about 6,000 patients are affected by BCG shortage.
The UK chose not to import alternate BCG like other European countries to deal with BCG shortage. Instead, the UK and MERCK had agreed that MERK would commit to supply 90% of what the UK used to receive from Merck before the shortage, and the UK took a strategy to reduce the number of BCG treatments. From 2013 to 2019, European Association of Urology Research Foundation conducted a clinical trial NIMBUS to assess whether a reduced number of standard-dose BCG installations are noninferior to the standard number and dose in patients with high-grade NMIBC. The standard BCG schedule was 6 wk of induction followed by 3 wk of maintenance at 3, 6, and 12 mo (15 instillations). The reduced frequency BCG schedule was induction at wks 1, 2, and 6 followed by 2 wk (wks 1 and 3) of maintenance at 3, 6, and 12 mo (nine installations). The reduced frequency schedule was inferior to the standard schedule regarding the time to first recurrence. Further recruitment of patients was stopped immediately to avoid harm in the reduced frequency BCG arm. So, the UK scrapped their strategy to reduce frequency of BCG and has come up with the current protocol to deal with BCG strategy. The current protocol is described below. The protocol is different for very high risk NMIBC and high risk NMIBC. Also, the UK is working with MERCK and the Department of Health and Social Care for diversification of the UK’s BCG supply. Note that the UK is recommending full dose as Canada vs 1/3 dose which the US is recommending. Below is the current recommended protocol in the UK.
For Very High Risk NMIBC (T1HG +/- CIS)
Routine supply Give induction BCG and up to 8th batch of 3 doses of maintenance BCG. Total is max 30 BCG treatments
Limited supply Give induction BCG and up to 2nd batch of 3 doses of maintenance BCG, if available. Total is 12 BCG treatments
Supply unavailable excluding patients with pTis, consider induction & maintenance therapy with intravesical chemotherapy
For Standard High Risk NMIBC (solitary TaHG )
Routine supply Give induction BCG and up to 2nd batch of 3 doses maintenance BCG. Total is max 12 BCG treatments.
Limited supply Give induction BCG and up to 2nd batch of 3 doses of maintenance BCG, if available. Total is 12 BCG treatment
Supply unavailable offer intravesical mitomycin chemotherapy +/-maintenance treatment
If Canada did not use alternative BCG and still wanted to give full dose Tice-BCG, Canada could have had a similar strategy as the UK, but administration may be challenging especially in community hospitals unless the guideline is top down enforcement. In the UK, the decision of NHS (National Healthcare Service) is made, the decision trickles down to local hospitals in the nation. Canada’s health care system is different. Provincial government decides
France, Italy, and Spain
European countries except the UK chose to use alternative BCG. It is not certain if all European countries who were using Tice-BCG completely switched from Tice-BCG to alternative BCGs or are still continuing to use Tice-BCG.
There are two BCG manufacturers in Europe, i.e. AJVaccines in Denmark and Medac in Germany. In Denmark, their national BCG lab had been producing BCG (Danish-1331 strain) for many years for vaccine and for bladder cancer, but it was sold to AJVaccines a few years ago. Their Danish-1331 strain BCG is being sold as VasiCulture. A vial comes in 30mg and full dose is 120mg. AJVAccines is a pre-qualified supplier of BCG vaccine to WHO.
Medac is a German company, established in 1970. Medac is specializing in therapeutic agents for the treatment of oncological, urological and autoimmune diseases. Medac sells their BCG for bladder cancer treatment only and does not sell its BCG for vaccines for tuberculosis with some exceptions. MERCK also sells their BCG for mainly for bladder cancer treatment. Medac’s BCG is sold under BCG-MEDAC which is based on RIVM strain. A dose of BCG-MEDAC comes in only 50mg. It is noted that though both TICE-BCG and BCG-MEDAC come in 50mg in vial and a 50mg is full dose, they are different drugs. For example, A vial of 50mg of Tice-BCG contains at least 100 million and at most 800 million CFUs of BCG bacteria, but BCG-MEDAC of its 50mg vial contains at least 200 million and at most 3 billion CFUs of BCG bacteria. A study which compared Tice-BCG and BCG-Medac showed that when patients had second TURBT and maintenance treatment, recurrence rates were 23.1 with Tice-BCG and 38%, showing Tice-BCG was superior to BCG-Medac in terms of recurrence rate. Recurrence for high risk patients likely means cystectomy unless patients have the option to have treatment for BCG unresponsive. The access to the treatment for BCG Unresponsive is less for patients being treated with Verity-BCG than patients being treated with Tice-BCG, which will be explained later.
FRANCE
France with a population of 68 million prescribes about 8,000 vials of BCG-Medac each month. One time only 700 vials were available per month.
Given the new difficulties in supplying BCG Medac for the treatment of bladder tumors announced from March 2021, the Medac laboratory is reinstating a quota from February 1, 2021, in agreement with the ANSM and the AFU. Since the end of 2020, the supply of BCG Medac has been based on a single factory in Europe. These supply difficulties are the consequence of a reorganization of production in this factory in order to increase the yield and the sustainability of production in the long term. All the countries using the Medac specialty are therefore impacted and a return to a normal situation is not expected before the end of 2021.
The quota is based on a nominative allocation of BCG Medac stocks using a scale of points allocated according to predefined clinical criteria (score). This is the same quota as that put in place in 2019 and whose effectiveness has been demonstrated by the absence of reported cases of cystectomy (bladder removal) imposed for lack of BCG. A stricter quota is not excluded in the event of less availability of the specialty in the months to come.
The quota based upon a scale of points of individual patients is as follows.
Presence of carcinoma in situ (CIS): 6 points
High Grade / Grade 3: 5 points
Stage T1: 4 points
More than 8 tumors: 3 points
Tumor dimension ≥ 3 cm: 3 points
Tumor recurrence within less than a year: 2 points
Age ≥ 70 years old: 2 points
Patient ineligible for radical treatment (surgery / radio-chemotherapy): 4 points
Impossible access to thermo-chemotherapy: 1 point
Patient participation in a clinical trial imposing BCG: 4 points
Total out of 34 points.
In addition, one of the following patient’s status is checked if it is induction initiation, induction in progress, interview initiation, maintenance in progress. Lastly a quantity of patient vials was requested.
I think this quota system enables BCG to be used according to the risk level of patients. The best of all, medical authorities were monitoring the impact of the quota system and found out that there were no cystectomy (bladder removal) for lack of BCG. I think this quota system is much better than the quota system which was implemented in the US or Canada which Merck depended upon its distributors or local branches to supply according to the past demand.
The fact France was able to implement the centralized decision on who should get BCG at the time of the shortage is likely because of France’s healthcare system which is more controlled at national level.
The problem with the quota system MERCK used in the US was that the quota depends upon the previous demand from hospitals. The more BCG vials a hospital uses, the more BCG vials the hospital gets. In the US, many community hospitals did not follow the ⅓ dose protocol which was recommended by the consensus. Instead, they used full doses, which led to an unfair share of BCGs among different hospitals. I think this is a flaw of the quota based allocation of supplies based upon the past usage volume. Had the US chosen a centralized BCG allocation system based upon how risky patients’ NMIBCs were, it could have a better outcome from the current BCG shortage.
France experienced BCG-Medac shortage as the BCG production was the demand for BGC-Medac exceeded the production capacity and the production was interrupted at Medac’s production plant while Medac upgraded the plant. However, the BCG shortage was not systemic and Medac was able to resolve the shortage problem. To deal with short term sporadic shortage, Medac arranged importing alternative BCG with consent of The French National Agency for the Safety of Medicines and Health Products. First, AJVaccine Danish-BCG was imported. When it became unavailable, SII-Onco-BCG was imported. The BCG-Medac shortage lasted two months and once the shortage was resolved, BCG-Medac terminated the importation of alternative BCGs. In this way, patients who had to use different BCG than BCG-Medac were contained in terms of number of patients and duration of patients were treated with different BCG. This would also limit the impact to patients efficacy and side effects by different BCG. So, at present, in France, BCG-MEDAC is the main BCG and if it encounters sporadic shortage, Medac takes a control and uses Danish-BCG of AJVaccine or SII-Onco-BCG temporarily to cover the shortage.
Italy
In Italy in 2020, with a population of 60 million, approximately 25,500 new cases of bladder cancer were diagnosed (20,500 among men and 5,000 among women).The 5-year survival is equal to 79%, without significant gender differences (80% in men, 78% in women). Since France prescribes 8,000 BCG each month, I expect Italy to prescribe about 7,000 BCG a month.
Italy seemed to have three BCGs approved for bladder cancer early on, i.e. Sanofi Connaught BCG, Merck Tice BCG and Medac RIVM BCG. But, MERCK’s subsidiary in Italy was not allowed to import Tice-BCG until Nov 19, 2014.
Between 2012-2014, when Italy experienced the first wave of BCG shortage, Italy did not use alternative BCG strains but rather prioritized the usage of BCG to high risk patients.
As the BCG shortage continues and Sanofi Connaught BCG becomes unavailable, sales of Tice BCG and BCG-MEDAC have increased. Yet, BCG shortage continued. In Italy during BCG shortage, initially BCG was prescribed only in the most serious of three levels (modest, moderate and high). But in 2015, the levels have been changed to only two (low and high). BCG continued to be prescribed in the high level, on that today this could also include cases in which the drug is not essential. This had contributed to growing demand at a time when BCG was already in short supply.
Due to further demand for more BCGs, AIFA (The Italian Medicines Agency) authorized the importation of the analogous medical product SII-Onco-BCG 40 mg from Serum Institute of India after verifying the necessary document.
In 2019, Sanofi Connaught BCG became permanently unavailable. Merck’s production capacity in a single manufacturing plant in North Carolina could not produce enough BCG and European countries who decided to rely on Merck Tice BCG after Sanofi Connaught BCG faced extreme BCG shortage.
There was a big article in the newspaper “Cancer, the complaint: “My father without therapy because the drug is missing” dated July 2020. The article says “Cancer patients waiting for a drug (BCG-MEDAC) that has not been found for month and also its possible alternative (Tice-BCG) is lacking. It happens in Italy in a hospital in the capital. The case is denounced by the daughter of a 73 year old who does not want to give up on what can happen in a country with the health service judged, internationally, to be among the best in the world”. I am sure Canadians felt the same.
AIFA stated that “The BCG-MEDAC medicine has been lacking since April 2019 due to production problems of the company holds marketing authorization. The Medac owner announced on June 26, 2020 that the medicine will return available albeit with small quantities and therefore in quota distribution as early as mid-July. In fact, in Rome, other large institutions still have stocks of both drugs, but the problems also concern the rest of Italy,. Eventually, Medac seems to have taken ownership of BCG shortage in Italy and Medac arranged their subsidiaries in Italy to import alternative BCG from AJVaccine Danish-BCG and SII-Onco-BCG when BCG-Medac became in shortage. A case in point is when BCG-MEDAC was expected in shortage during the recent upgrade of MEDAC BCG plant in Hamburg, Germany.
Medac Pharma Srl is authorized to import the medicine
SII-Onco-BCG (BCG for immunotherapy BP) 40mg 3 vials
3,000 packs of 3 bottles Lot 1130G039, deadline Feb 2023
Medac Pharma Srl must send at least one leaflet in Italian to each facility receiving the drug, The drug be supplied without making any changes to the selling price in Italy to the drug “BCG-MEDAC” RIBM strain sx10**8 up to xx10**9 variable units (CFU).
MEDAC recommends the standard BCG treatment protocol for high risk NMIBC, i.e. 6 weeks induction and 3 years of 3 weeks maintenance totaling 27 doses. In terms of mixing BCG, MEDAC states as follows.
“Therapeutic schemes with different BCG strains have been tested in clinical studies carried out on a large number of patients. At this point it is not yet possible to establish which of these regimens is more effective than the others.” This was an honest opinion from BCG-MEDAC. It should be noted that two studies based upon Italian hospitals concluded Tice-BCG exceeded BCG-MEDAC and Connaught BCG in terms of recurrence free period when maintenance treatment with BCG is provided.
In summary, Italy has experienced BCG shortage dating back to 2012 and continuing till early 2022. At present, BCG MEDAC seems to be the majority if not all of BCG administered in Italy. MEDAC Pharma took ownership of the BCG shortage, and when their production was interrupted, MEDAC subsidiary in Italy imported different BCG, initially from Denmark, later from India for a temporary period, and terminated the importation once MEDAC’s BCG production increased. This was possible partly because MEDAC is a company of 1,000 employees and had financial power and resources to deal with the matter. I could not find if Italy had implemented the centralized BCG allocation based control system as France did, which made sure higher risk patients will get BCG regardless of where the patient lives.
SPAIN
Among a population of 47 million, 20,000 cases of bladder cancer are diagnosed each year 1 76% are diagnosed as NMIBC in Spain. Portion of new patients diagnosed with G3 tumors are 43.7% and the portion of recurrent patients with G3 tumors is 27.7%. Note that it seems that in Europe G1.G2,G3 classification for NMIBC grade are used more often than NA though my hospital in Fraser Health Authority still uses G1,G2,G3. 2004 WHO classification of grade of NMIBC is LG, HG, so part of G2 is classified as LG and part of G2 is classified as HG.In July 2017, Merck informed the Spanish Agency for Medicines and Health Products (AEMPS) of a delay in having the next batch manufactured at the Sanofi BCG plant and has very limited supply till August. Until the supply of BCG becomes sufficient, the Spanish Urology Association recommended the following.
For patients who are on a maintenance regimen, BCG treatment will be suspended until there is a greater product availability.
BCG will be limited to the 6 weeks induction period. Maintenance will be performed with intravesical chemotherapy.
The initiation of BCG treatment will be a prioritized base.
After Sanofi Connaught BCG, MERCK Tice became the main BCG in Spain. In January 2020, The Spanish Agency for Medicine and Health Products (AEMPS) reported the supply problems of authorized BCGs, and alternative BCGs were considered. One is BCG-MEDAC by MEDAC in Germany and BCG Culture by AJVaccine in Denmark. BCG-Medac comes in 1 vial of 50mg as full dose and BCG Culture comes in 4 vials of 30mg (120mg) as full dose.The Spanish Urology Association came up with a recommendation and the estimated BCG dosage required.
Total G3 cases/year requiring BCG. 7,294 patients. If only 6 weeks induction treatment is provided, it would require 43,758 annual doses.
At first, Spain authorized Sanofi Connaught BCG, Tice BCG and Vejicur (Tice-BCG).
Obtained a Tokyo strain BCG because it was backed by published study, as authorized BCGs.
Concerned that in some cases, the strain with which the induction begins may not be the same strain with which it ends.
Basic recommendations by the Spanish Urology AssociationThe quality of TURBT must be maximized as it is the first and most important treatment that by itself improves the prognosis of patients.
The use of a cystoscope and narrow band TURBT, Spies(?), or bluelight if available be used to improve the quality of TURBT at least if the most complex ones.
Immediate postoperative instillation of Mitomycin C,
The combination of intravesical chemotherapy with hyperthermia.
The use of EMDA, a system that uses electric current to enhance the tissue penetration of intravesical chemotherapy agents.
Dose reduction to ⅓ for intermediate risk NMIBC.
NEWLY DIAGNOSED PATIENT WITH HIGH GRADE BLADDER TUMOR, GIII or CIS 7A clinical report of the patient for whom we request BCG will be sent to the Hospital Pharmacy.. From the Pharmacy, it is sent to the AEMPS for authorization. Once the request is approved and while there are stocks, the Agency will send 6 vials only for the induction period. Dose reduction is not advised.
If BCG is not available, for whatever reason, it is recommended to proceed as follows:
1.-Patients with very high risk of progression (>45% at 5 years, score in the EORTC tables >13). Ta-1G3 or Tis tumors
Cystectomy or various intravesical chemotherapies
2- patients with high risk of progression (>17% at 5 years) Ta-1G1-2 with > 8 sites or Ta-1G1-2 with 3 associated factors (recurrent, > 3cm, multi sites < 8 tumors)
Intravesical chemotherapies
Patients who have started weekly induction with BCG,A clinical report of the patient for whom we request BCG will be sent to the Hospital Pharmacy, (see annex 1) and reflecting the number of containers required to complete the 6 weeks of induction. From the Pharmacy, it is sent to the AEMPS for authorization. Once the request is approved and while there are stocks, the Agency will send the necessary vials to complete the induction period. Dose reduction is not advised.
PATIENTS ON MAINTENANCE REGIME .BCG instillations will be suspended regardless of when they are. The possibility of performing monthly maintenance treatment preferably with chemohyperthermia or EMDA if available is left to the urologist’s judgment, despite the fact that there is no scientific evidence to support that maintenance chemotherapy after BCG induction can prevent tumor recurrence.
NEWLY DIAGNOSED PATIENTS, MEDIUM RISK OF PROGRESSION (6% in 5 years, score 2-6 of the EORTC tables) AND MEDIUM-HIGH OF RECURRENCE (62% in 5 years, score 5-9 of the tables of the EORTC ). Ta-1G1-2 tumors with 2 associated factors (recurrent, ≥ 3 cm, multifocal < 8 tumors).
BCG will not be requested
Intravesical Chemotherapy
CONCLUSIONSThese recommendations have been made based on published scientific literature, knowing that in the situation in which we find ourselves, the level of scientific evidence is not high 9 .
This may mean that in some cases we are over-treating patients with early cystectomy, and in others under-treating them because maintenance treatments are not available. We must emphasize strict follow-up of all patients so that they can benefit from the best possible treatment at all times, not delaying cystectomy in those with the highest risk of progression.
The applicability of these recommendations is only valid while the situation is generated by the low or null availability of BCG lasts.
In Summary, in Spain, the approval of BCG usage was centrally controlled by the Spanish Agency for Medicines and Health Products (AEMPS) which is similar to what France used though the format is different.AUSTRALIA & New Zealand
Australia and New Zealand are still using MERCK Tice strain Onco-Tice BCG – Confirmed by MERK Subsidiary in Australia. t seems that both countries are supplementing with other BCGs from other countries only when Onco-Tice become in shortage.
AUSTRALIA
At the first onset of BCG shortage started in 2014, Australia tried to navigate BCG shortage by reducing dosage, i.e. ⅓ . But, it seemed they quickly opted to import alternative BCG using the Special Access Scheme. I see that Australia granted importation of BCG-Medac from Germany in 2018 and Danish-BCG from Denmark in 2021.
Australia’s population in 2021 was 25.70 million. Cancer Australia – the government estimated 2,470 males and 749 females total of 3,219 Australians would be diagnosed with bladder cancer, and 1,043 death from bladder cancer which is 32.5%. According to Canadian Cancer Society, it is estimated that in 2022, in Canada, 13,300 Canadians would be diagnosed with bladder cancer and 2,500 would die, which would be 18.8%. American Cancer Society estimates that in 2023, 82,290 (m=62,400,f=19,870) will be diagnosed with bladder cancer and 16,710 will die, which is 20,3%.
There is an urology association for Australia and New Zealand combined. So, I expect the approach to alleviate the BCG shortage will be similar in two countries.
On April 29, 2015 Department of Health and Aged Care – Therapeutic Goods Administration announced that both Sanfi subsidiary in Australia and Merck subsidiary in Australia submitted a Medicine shortage notification for Immucyst (Connaught strain), OncoTice (Tice strain) BCG, citing that the shortages are due to supply disruptions.
The same government notice stated that alternative products are available under the Special Access Scheme. To access alternative, please contact your hospital pharmacy.
Australia chose to import alternative BCG when Sanoffi Connaught and Merck Tice became scarce..
In 2018, Therapeutic Goods Administration in Australia has granted permission for the importation of an alternative BCG vaccine for treatment of bladder cancer via the Special Access Scheme. Namely BCG-medac, produced in Germany by Medac. Merck itself have altered the distribution of the BCG vaccine to ensure fair allocation and prevent stockpiling by allocating stock to countries based on historical demand as well to wholesalers within.In 2021,
Australia has granted permission for the importation of Danish-BCG, produced in Denmark by AJVaccine.
ANZUP (Australia and New Zealand Urological and Prostate Cancer Trial Group). Is doing clinical trial of BCG + Mitomycin. MERCK subsidiary in Australia has been providing BCG to upto 500 patients in the clinical trial in spite of the BCG shortage. So, it is apparent that Tice-BCG is still the main BCG used in Australia.
NEW ZEALAND
I found a POD cast dated back December, 2014 a patient and urologist talking about BCG shortage in Auckland New Zealand. A female patient was told at 3rd installation of 6 weeks induction treatment that the dosage would be reduced ⅓ due to the shortage.
On January,2015, Merck subsidiary in New Zealand announced to health professionals in New Zealand that further interim measures have been taken to help with continuity of supply for BCG Vaccine to New Zealand. Merck and Tel Arai BioFarma,the distributor of Serum Institute of India and secured SII-Onco-BCG till Tice BCG is shipped in March
On Feb 3, 2021, Waikato Hospital, Hamilton, New Zealand published their clinical study comparing side effects experienced by patients treated with Tice-BCG and patients treated with SII-Onco-BCG. The clinical study says due to the worldwide shortage of OncoTICE, we made the decision to use SII Onco BCG as the alternative. We have identified a higher number of new and existing patients describing more symptoms of bladder irritability with the use of SII Onco BCG, leading to the termination of treatment.
This study is the only study I have found so far that SII Onco-BCG caused more severe side effects than Tice-BCG, which led to the termination of treatment. It is noted that in this case, hospital prescribed 3 vials of 40mg as a dose, where in Canada, 2 vials of 40mg are used as a dose.
Other countries – It is very time consuming to find information of other countries, so I limited to Brazil as Brazil seems to be importing BCG vaccine and SII-Onco-BCG most among countries SII export its BCG.
Brazil
According to estimates released by the National Cancer Institute (Inca), about 10,000 Brazilians are diagnosed with bladder cancer every year. The number is smaller than Canada, which estimates 13,000 per year. Considering the population of Brazil is 1213 million vs 37 millions of Canada, something is wrong with the number. .
Brazil had been producing its own BCG vaccine and BCG for bladder cancer with Morneau strain BCG for nearly 100 years. But, There has been a shortage of BCG vaccine and BCG for bladder cancer for several years. I recall a young man was posting in the discussion forum looking for BCG for his sister in Brazil as there could not find BCG in Brazil, and though individual was allowed to import BCG from other countries, the cost of importing, customs, the price of BCG was too expensive that they could not afford it in Brazil.
Brazil was planning to build a new vaccine production facility in Rio De Janeiro, the capital of Brazil over 30 years ago. The current production plant had many quality issues.
As the only BCG manufacturing became banned from manufacturing BCG and the BCG manufacturing plant won’t be ready in near future, infants were not able to receive BCG vaccine and patients with bladder cancer were not able receive BCG treatment. Accordingly, Brazil allowed importing of BCG vaccine and SII-Onco-Tice from SII in India bladder cancer through a registered Brazilian company.
Nov 2019 article says
The professor says that he had already made five of the six weekly applications of the medicine, a standard procedure to prevent the recurrence of the tumor after its removal.
“I went to the hospital to take the last dose, but they informed me that the (Immuno) BCG was over and there was no forecast for a return”, says Netto.
called distributors in every state in the country, but I couldn’t find Imuno BCG. So I joined a group of patients and managed to buy from a person who also had cancer and kept two vials”, she says, who lives in Rio de Janeiro . On the market, each ampoule of the medicine costs around R$ 700.
However, the retiree still needs to use the medicine for at least three years, with new monthly applications. For now, its treatment is paralyzed by the lack of immunotherapy on the market. “My father discovered the cancer at an early stage. And, according to the doctors, treatment with BCG has a great chance of improvement. It is a desperate situation not to find the medicine, a total disregard for people with the disease”, says Cíntia.
In 2020, Journal of Band posted in Youtube that Brazil started importing SII-Onco-BCG as Brazil’s own BCG is not available. I have noticed that there have been many exporting of SII-Onco-BCG to Brazil in recent years.
Yet, a few patients posted to the Youtuve about unavailability of BCG for bladder cancers in Brazil.
Antonio Cari May 2022, I am still not be able to access BCG
Elizabeth FelicidadeFeb, 2022 Nine months later, it is still missing, so important, it avoids relapses, this situation is very difficult
Maria do Carmo Silva
Reply So it is. My mother is already going to the third surgery precisely because there is no treatment in hospitals. This could have been resolved right after the first surgery, but no hospital has the necessary medication. A patient she befriended is about to have her fifth surgery, poor thing. This is absurd!
So, it looks like even Brazil started importing SII-Onco-BCG, the BCG shortage is not completely resolved.
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