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Homepage – Forum Forums Non-Muscle Invasive Bladder Cancer A thought on two different BCGs for the treatment for Non-muscle invasive BCa

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  • #42726
    Joe
    Participant

    Now, the official version of availability for two BCGs from Tice strain from MERCK and Moscow/Russian strain from VERTY has been announced.    When I read it, I kind of scratch my head because it is not exactly what I had anticipated.   It is a bit complicated, but I have thought it is important for patients to know what it is and what the implication is for current and future NMIBC patients who require BCG treatment.  So, I try to disseminate the information from a patient’s point of view.   FYI,  Merck Tice strain BCG is marketed  as Onco-Tice (R) and it is manufactured in Durham, NC, USA.  VERITY-BCG is Moscow/Russian Strain which is manufactured by Serum Institute Of India Pvt. Ltd, in Pune, India, and it is marketed in Canada by VERITY Pharmaceutical.

    1.  Conditional Approval by Health Canada

    Heath Canada had approved VERITY-BCG for TaHG and T1HG papillary type non muscle invasive bladder cancers  but not with CIS (Carcinoma In-situ) or CIS only.  It means if we are diagnosed  CIS or CIS + (TaHG or T11HG), Merck Onco-Tice is the only BCG we should be receiving.     What about when we are diagnosed with TaHG or T1HG?   Do we have an option to choose either Merck Onco-Tice or VERITY-BCG?   Or is it up to the urologist to choose?  I could not find anything about this except BC and Alberta.  It is nice if patients in other provinces can find out and post its information here.

    BC Cancer Agency issued a memorandum  that OncoTICE should continue as the default brand and that VERITY-BCG is to be used when OncoTICE is not available.  Also it mentions that the same BCG should be used for the whole BCG treatment but it is okay to use the different BCG in case  the original BCG becomes unavailable.   This is clear.

    Alberta Heath Service Guideline Resource Unit published its guideline on Non-muscle Invasive Bladder Cancer with  effective date : January,2020.  Under BCG administration section, Item D.  says BCG (Merck 1 vial; Verity 2 vials) diluted in 50 mL normal saline instilled via catheter weekly x 6 weeks.      No other information were provided.  This is not clear.

    The main reason for VERITY-BCG receiving conditional approval seems to be  the lack of a large clinical data and for that, Health Canada has requested Verity to complete a clinical trial involving about 520 patients, spanning over 3 years within a certain time frame.  I will cover this matter later.

    Full dose (FD)

    The consensus report suggests the patients should be given full doze for 6 weeks induction course and the maintenance course which can last 36 months.

    FD of Merck Tice strain BCG is 50 mg, and FD for VERITY Russian strain BCG is 80 mg.

    All BCG strains available in the world are the descendants of the master seeds BCG still cultured at Pasteur Institute  in Paris. Because BCG are live attenuated bacteria which are used as a vaccine for Tuberculosis, they mutate and its efficacy and side effects are not exactly the same.  That is why WHO enforces quality control on BCG producers so the efficacy and the side effects are within a certain range. One key parameter for  WHO’s quality control is the number of BCG bacteria in a dose, and it is expressed in CFU (Colony Farm Units).  I have noticed that CFU gets much attention in BCG for vaccines, but not much studies are done for BCG for bladder cancer. There have been a few studies comparing different strains in full dose, and dose reduction to deal with BCG shortage such as the case in the USA.  Anyway, the point is that FD of MERCK Tice strain BCG is 50mg and FD of VERITY Russian strain BCG is 80 mg (40mg x 2). So, technically, given both BCG have the same CFU per mg,  those patients who are treated with VERITY Russian strain BCG get 60% more numbers of BCG bacteria into the bladder compared to those patients who are treated with MERCK Tice strain BCG. Most patients would think that FD of VERITY Russian strain BCG has higher efficacy but also higher toxicities (side effects).  I think that the consensus among urologists are that they are similar enough and the benefits to the patients from preventing recurrence and progression because of the BCG shortage outweigh the differences,  but to prove it,  Health Canada had requested a large-scale clinical test. Incidentally the similar clinical trial to compare MERCK Tice strain BCG vs Tokyo-172 strain by Japan BCG laboratory had been completed. The trial involved 1000 patients and over 150 testing sites in the US.  The trial has been completed, so we should expect the result of the study soon.

    It is interesting to know that the Sanofi Connaught strain BCG, which the Sanofi plant in Ontario had been producing for bladder cancer, had 81 mg in a vial.  When Sanofi shut down its production facility in 2012 and eventually exited from BCG business in 2016, many countries faced the shortage as Sanofi was a major supplier for BCG for bladder cancer in the world, and sharing the NA market and European Market with MERCK.  So, many countries had to switch from the Sanofi Connaught strain BCG (FD 81mg) to MERCK Tice Strain  (FD 50mg).  In this case, the number of BCG bacteria that was introduced to the bladder had been reduced by 60%.  I have not been able to find studies on the impact of this change.  One small study was done to compare Sanofi Connaught strain BCG vs MERCK Tice strain BCG, and it showed slightly better efficacy of Sanofi Connaught strain BCG on recurrence.  So, FD (80mg) of VERITY Russian strain BCG may show better efficacy in terms of recurrence compared FD (40mg) of MERCK Tice strain BCG, but it may show higher toxicity,

    I do not have detail comparison data in terms of toxicity between 80 mg and 50mg, but a recent study done at a hospital in New Zealand, who had substituted MERCK Tice strain BCG ONCO-TICE(R) with SII Russian strain BCG ONCO-BCG(R) because of BCG shortage says “

    “Due to he global shortage of OncoTICE(Merck, USA) we utilized SII Onco BCG (Serum Institute, India) which VERITY imports it and market under its trade name VERITY-BCG as our substitute. However, we noticed higher discontinuation rates and severe complications in our patients with the use of SII Onco-BCG, one of them described with our case below.”  I am not sure if the full dose of SII Onco-BCG is 80mg or 120 mg as some countries like Philippine seems to prescribe 120 mg of SII Onco-BCG. Anyway,  MERCK in New Zealand issued a notification of availability of SII Onco-TIce BCG on January 28, 2015 to healthcare professionals

    “Te Arai Biofarma has secured supplies of SII-ONCO BCG. The product is not currently registered in New Zealand so will therefor have to be prescribed under section 29 .Note also that the dosage and administration of SII-ONCO BCG is not the same as for ONCOTICE: 3 vials of SII-ONCO-BCG is to be reconstituted for administration. See below for the product description.  3 vials equas to 120 mg.

    Product Name   SII-ONCO BCG (40mg/ml, 1-19.2×10**8 CFU)a

    Pharmacode      =2474239

    PackSize           3 vials per pack

    Price and subsidy  $149 per pack

    We expect that the volume of SII-ONCO BCG that is to be available will be sufficient to clear back orders and to last, at usual demand volumes, until the next shipment of ONCOTICE is available in March. ”

    FYI, Section 29 is the New Zealand Medicines Act allows the sale or supply of unproved medicines.  It is my understanding Australia took a similar approach to import BCG rather than going through an approval process.  I saw an article one healthcare authority in Australia imported Medac RIVM strain BCG for bladder cancer from Germany.

    As conclusion, personally, I would like to know what I am getting into the bladder.  Now two BCGs are available for TaHG and T1HG patients. So,  the product information of  where the product was made, sufficient information of each BCG should be readily available to patients just like consumers can see on the product label when we buy our grocery, so a patient can participating in choosing the BCG  just as we were given a choice between Pfizer and Moderna vaccines when they are both available even though both are same mRNA based vaccines and the efficacy and the side effects are very similar.

    best

    • This topic was modified 2 years, 11 months ago by Joe.
    #42732
    Joe
    Participant

    Conditional Approval by Health Canada and its implication

    The main condition for VERITY-BCG (R) Russian strain BCG to be fully approved and to treat all high risk including CIS non-muscle invasive bladder cancers is to prove VERITY Russian strain BCG is not inferior to MERCK Onco-TICE (R) TICE strain BCG.   Intuitively, I expect the full dose of VEIRY-BCG (80mg) should have  higher efficacy and higher toxicity (side effects) than the full dose of MERCK-BCG (50mg) simply they share the same parent from the master seeds of Pasteur Institute in Paris, the BCG production process itself is not complicated except it is difficult avoid variability due to dealing with live bacteria, both BCGs have been used to treat non-muscle invasive bladder cancer patients in many countries, and Sanofi Connaught strain BCG (81 mg) showed better recurrence free survival rate than MERCK(50mg).

    But, the cost for the clinical trial which Health Canada has requested may not economically justify to VERITY Pharmaceutical share holders even to pursue the clinical trial as the dynamics of the future BCG market has chanced drastically when MERCK had announced in January, 2021 that their board of directors had approved the plan to add another new facility to increase the Onco-Tice Tice strain BCG to three times of the current production volume.  According to the announcement,  the new facility will be completed in 2026-2027.   At that point, there will not be shortage as we are seeing now, and I would expect those countries who are supplementing the shortage of MERCK Onco-TICE BCG with other BCG with different strains will go back fully to use TICE strain BCG.

    In the US, which is the biggest market for BCG for bladder cancer, in order to deal with the shortage, had taken a different approach to reduce the dosage to 1/2 and 1/3 for the treatment for high risk non-muscle invasive bladder cancer including CIS, and used intervesical chemotherapy such as Gemcitabine + Docetaxel when BCG was not available at all.  Meanwhile, in 2017 the US started the clinical trial to test Tokyo-172 strain BCG.  The clinical test which FDA approved was to compare Tokyo-172 strain BCG and Merck TICE strain, involving 1,000 patients and 174 test sites, which is almost the same as the clinical trial that FDA approved on September 8, 2021 for VERITY Pharmaceuticals to compare Russian BCG-I strain vs TICE strain, involving 540 patients at multiple test sites.    It took nearly 5 years but it looks like the clinical trial SWOG 1602 has completed and we should expect the result soon, and I expect the efficacy of Tokyo-172 strain BCG will be somewhat higher but the toxicity will be also higher because the full dose of Tokyo-172 strain BCG is also 80mg.

    The difference between SWOG-1602 clinical trial for Tokyo-172 strain vs NCT05037279 which is registered clinical trial of VERITY Russian strain BCG is the sponsor.   SWOG-1602 was sponsored by SWOG (formerly the Southwest Oncology Group) is a National Cancer Institute (NCI) supported organization that conducts clinical trials in adult cancers.  JAPAN BCG Laboratory just supplied their Tokyo-172 strain BCG during the clinical trial.

    The cost of running a clinical trial is very high.  Johns Hopkins Public Health School it costs in average US$6M to run a clinical trial with less than 100 patients and US$ 77M for the trial with more than 1,000 patients.  SWOG-1602 which involved 1000 patients and 174 testing hospitals would have costed near $30-$50M.  The only reason SWOG-1602 clinical trial was possible is because all those testing hospitals and doctors basically provided the testing free of charge.   On the other hand,  according to the FDA clinical trial web site,  VERITY Pharmaceutical is  the sponsor for the clinical trial, meaning that VERITY Pharmaceutical has to pay to those hospitals to conduct the testing, which would cost $15-25M as the clinical trial is required to involve 540 patients at multiple test sites and the clinical trial  would take similar length (4+ years) same as SWOG-1602.    I do not see investing $20 million dollars for the clinical trial makes sense when there are no demand for additional BCG when the clinical trial.    The clinical trial site shows NCT05037279 started in September, 2021, but currently it is not recruiting patients and no testing sites have been identified.

    SWOG-1602

    In addition to compare Tokyo-172 strain BCG vs MERCK Onco-TICE Russian Strain BCG, SWOG-1602 clinical trial has tested if getting a BCG vaccine shot in arm prior to BCG induction  course with Tokyo-172 strain will improve the efficacy compared to those who had Tokyo-172 strain BCG only.   The preliminary data shows 30% improvement in recurrence free survival rate among patients who had a BCG vaccine shot, which I find it significant finding.  Though the test was done with Tokyo-172 strain, I think it should apply to all BCGs with different strain.   See the attached slide  from the presentation by Dr. Christopher Ruan , Executive Officer of SWOG.

    Finally, I have not conflict of interest with any party mentioned in this posting.    I am just posting this as a patient who was diagnosed with non-muscle invasive bladder cancer and as a patients advocate for fellow patients, who believes the information helps patients understand the whole situation in regards to the recently announced consensus statement for having two BCGs for bladder cancer patients in Canada.

    Though I have spent considerable of time in researching this subject and I believe the information I had provided is accurate, but it is always possible that some information can be in accurate such as an estimated cost for a specific clinical trial and I apology in ahead for any errors I might have  included in the posting.  So,  I would suggest to readers to read the posting with a huge pinch of salt. 🙂

    Preliminary Data from SWOG 1602

    • This reply was modified 2 years, 11 months ago by Joe.
    #42742
    Joe
    Participant

    Tokyo-172 strain BCG

    So, the preliminary result for the group to test efficacy of recurrence free survival rate of  SWOG-1602 clinical trial shows the improvement of BCG vaccine + BCG over BCG alone using Tokyo-172 strain BCG. This group had total of 55 patients.  The observation lasted 5 years.  It did not show about the side effects, but if the side effects were were not in acceptable range, this study was terminated.   This indicates high possibility for Tokyo-172 strain BCG for high risk NMBIC including CIS  will be approved by FDA in near future   So, we may  need to be thinking ahead how  it going to affect patients in Canada when Tokyo-172 strain BCG is approved by FDA and becomes available in the USA for all high risk non-muscle invasive bladder cancers including CIS

    Different countries — Different strain BCGs

    Canada & USA:   There were two BCG producers, Frappier lab with Frappier strain BCG  in Laval, Quebec and Connaught lab with Connaught strain BCG in Ontario.   Sanofi took over BCG business from Connaught lab and started BCG vaccine business.   The first BCG for bladder cancer which was by FDA is Sanofi Connaught strain TheraCys(R) in May 1990 for CIS.  In March 2000,  Frappier strain BCG  PACIS(R)  was approved by FDA. PACIS(R) was discontinued.    Onco-TICE(R) BCG was approved in August 1990 by FDA.

    AJ Vaccine (Denmark) Danish strain –  Denmark

    MEDAC (Germany) BCG-medac RIVM Strain – Germany

    Sanofi (Canada) ImmuCyst Connaught strain  – France, UK  *1

    MERCK (USA)  OncoTice Tice strain – Austria, Sweden, Spain,Portugal, Poland, Italy, Norway, Finland, Germany, Belgium, Cypress, Greece   also Australia, New Zealand  *1

    SII (India) ONCO-BCG Russian strain –  Kenya, Greece, Philippine, Cyprus, Turkey, Venezuela, UK, UAE, Sri Lanka, Belize, Algeria, Columbia, Kurdistan, Lebanon, Jordon, Cuba, Tajikistan, Mauritius  *2

    Green Signal Bio Pharm (India) UROVAC Danish strain – Saudi Arabia, Nepal, Lebanon, Switzerland, Papua New Guinea *2

    Brazil  the Fundação Ataulpho de Paiva (non profit foundation) Monreau Strain  – Brazil

    Japan BCG Laboratory Immunobladder Tokyo-172 strain  – Japan, Taiwan, Hongkong, Korea

    *1 Europe :  Based upon European Medical Agency published in October, 2018 below were approved BCGs for bladder cancers.

    *2 Based upon the exported documents from India 2015-2016.

    TBD

    • This reply was modified 2 years, 11 months ago by Joe.
    #42744
    Joe
    Participant

    SWOG-1602  Clinical trial –  Comparing  apples and oranges or comparing oranges and grape fruits ?

    The official tile of SWOG-1602 is ” S1602, A Phase III Randomized Trial to Evaluate the Influence of BCG Strain Differences and T Cell Priming With Intradermal BCG Before Intravesical Therapy for BCG-Naive High-Grade Non-muscle Invasive Bladder Cancer”.    The study started on February  7, 2017 coinciding the announcement by Sanofi Pasteur exiting the business of BCG for bladder cancer.

    The study was divided into three groups

    GR1  INDUCTION: Patients receive TICE BCG solution intravesically once a week for 6 weeks. MAINTENANCE: Patients receive TICE BCG solution once a week for 3 consecutive weeks at months 3, 6, 12, 18, 24, 30, and 36 for up to 7 doses

    GR2 INDUCTION: Patients receive Tokyo-172 strain BCG solution intravesically once a week for 6 weeks. MAINTENANCE: Patients receive Tokyo-172 strain BCG solution once a week for 3 consecutive weeks at months 3, 6, 12, 18, 24, 30, and 36 for up to 7 doses

    GR3 PRIME: Patients receive Tokyo-172 strain BCG vaccine once ID. INDUCTION: Within 21 days, patients receive Tokyo-172 strain BCG solution as in Arm II. MAINTENANCE: Patients receive Tokyo-172 strain BCG solution as in Arm II.

    The study involved 1,000 patients at 174 study locations.   Sponsors and Collaborators were South Oncology Group and National Cancer Institute (NCI).

    The principle Investigator is Robert Svatek  South Oncology Group

    The background and update for SWOG-1602 had been published in July 2018 by Robert Svateck explains how they came to decision to have three different test groups and the reason why Tokyo-172 strain BCG was chosen to compare with Merck Tice strain.

    Background

    Prime/Boot immune response

    The concept for this study was prompted by the discovery that priming with subcutaneous BCG prior to intravesical BG instillations in pre-clinical models accelerated the entry of T cells into the bladder and improved response to BC by a French study in 2012.  Studies giving BCG vaccine and BCG concurrently did not improve recurrent free time, but a Japanese study showed the patients who showed positive on PPD (Purified Protein Derivative Skin) after receiving BCG vaccine improved the recurrence free period.   Note that as it has mentioned before the preliminary data from SWG-1602 have shown that those with positive on PPD after being injected with BCG vaccine had shown 30% increase or 60% improvement on 5 year recurrence free survival rate over those who were negative on PPD test.

    Different BCG strains

    Soon after establishing BCG’s antitumor efficacy, evidence from animal studies were published indicating that certain BCG strains may be more oncologically effective than others. To date, however, no adequately powered head-to-head trials have been conducted to examine the influence of BCG strain on clinical outcomes *1

    – A randomized trial with 142 found a significant greater 5 year recurrence free survival in patients with Connaught strain compared to TICE BCG.   However patients were not given maintenance and maintenance may have mitigated the difference.   * by 2014 by a French group and 2016 by US and other European Group.

    – A randomized trial with 129 patients showing similar recurrence free survival rates between  Connaught and Tokyo-172 strain supported SWOG’s decision to examine Tokyo-172 strain in SWOG-1602 trial.

    I have noticed that these studies examined the effects of different BCG strains.  But they do not mention what the quantity of BCG which was given to different strains.

    The full dose of BCG of MERCK Tice strain comes in a vial with 50mg.   Sanofi Connaught strain came in a vial with 81 mg BCG.  Japan BCG Laboratory Tokyo-172 strain came in a vial with 80mg BCG for full dose and  40mg for low dose.   According to the SWOG presentation,  Tokyo-172 strain BCG (80mg) have bee compared to Tice strain (50mg).  I do not know the exact reason why they did not choose to compare  Tice strain 50mg vs Tokyo-172 strain (50mg).  Then I think we are comparing an orange and  another orange.   But, one of goals, though it is not explicitly mentioned, is to find alternative BCG to supplement Merck Onco-Tice BCG to alleviate the current BCG shortage problem, so they want to choose the BCG candidate which most likely to succeed.  I think that as Tokyo-172 strain with 80mg had shown equivalent recurrence free survival rate with 80mg Connaught strain, and 80mg Connaught strain showed better recurrence rate then 50mg Tice strain BCG, 80mg Tokyo-172 strain was chosen as the comparator .

    So, now are we just comparing an orange and another bigger orange (grape fruits)?

    Tice strain and Tokyo-172 strain are different.  To what extent, I do not not know.   But we know that 50mg and 80mng are 60% different in quantity.    BCG quantity makes difference in the number of BCG bacteria which are introduced into the bladder.  The number of BCG bacteria in a vial is known.  Because it is almost impossible to have exact repeatability between batches in BCG production as BCG are live bacteria,  the producer of BCG vaccine are required to control  the number of bacteria to stay within a certain rage between batches.   In case of BCG vaccine, WHO requires that the variability of the number of BCG bacteria to stay within 4 folds.   The number of BCG bacteria is expressed in CFU (Colony Farm Units) which was explained before.      MERCK OncoTice Tice strain BCG says 1-8×10**8 CFU per 50mg vial on its label  indicating their variability between batches of 8 folds.  SII  ONCO-BCG Russian  strain says 1-19.7×10**8 CFU per 40mg vial on its label indicating their variability between batches is 19.7 folds.

    Interestingly, A Japanese study group (Osaka Medical College) mentions in their 2013 study that Tokyo-172 strain is unique to contain a higher number of CFU than other other strains given in the same quantity because the size of Tokyo strain BCG bacteria is smaller than other strains.   Subsequently, the group tested the low dose 40 mg of Tokyo-172 strain vs 80mg of Connaught strain.     The result, of  18 patients with Tokyo-172 (40 mg) and 20 patients with Connaught strain (80 mg) with 800 days follow up, showed the 1 year recurrence free survival rate 72.2% with Connaught strain and 83.5% with Tokyo-172 strain.  But longer term comparison show similar rates with a few percentage better recurrent free survival.  Also, the completion rate with Tokyo-172 was 17 patients (94.4%) and Connaught strain 14 patients (70%).   Incidentally, Japan was able to this study because Sanofi Connaught strain BCG had been approved in Japan and marketed by Nippon Kayaku (Japan Chemical Medicine) , a large pharmaceutical company in Japan.   So, two BCGs – Tokyo-172 strain and Connaught strain for bladder cancer were available in Japan before.

    What I have realized is the meaning of “clinical” trial, which means to validate hypothesis and determine if it can be used in real world of clinical environment.  Also,  I have realized  the importance of a large scale clinical trial in introducing a different BCG for bladder cancer because there are more differences than I initially thought in a full dose of different BCGs produced in different manufacturing facilities in different countries.

     

    #42758
    Joe
    Participant

    How other countries have been handling BCG shortage

    USA

    The US chose not to import BCG with different strain from other countries immediately, instead started the 5 year clinical trial to test Tokyo-172 strain to compare with MERCK Tice strain BCG.  Meanwhile, American Urology Association (AUA) recommended who should be receiving BCG full dose BCG and reduced dose according to the risk stratification of cancer types.   It is noted that MERCK had announced early 2021 that they would build additional production facility to increase the BCG production by 3 folds by in 5- 6 years, which should meet the global demands.  The detail of AUA guidelines during BCG shortage are listed at the bottom of this posting.

    I have followed how patients are reacting to BCG shortage though social media, discussion forums in USA such BCAN.   In the beginning, there were more cases that patients were told suddenly that BCG would not be available and some patients sought BCG at different hospitals.  The hospitals seemed not to know when the BCG would be available again.  In terms of dose reduction, for about a year so, urologists/hospitals could not do because there were no medical coding system to split the dose and still get paid by insurance company until the coding system allows to specify by mg.  Before urologists could specify 1 dose of Tice BCG (50mg), but  they can do split dose by specifying Tice BCG 1 mg x 17 each for 1/3 dose.  These days, questions from patients are something like  1/3 dose is effective as full dose.   I see feed back saying that they are willing to accept reduced dosage than other patients not receiving at all, with assuming that 1/3 dose was recommended with scientific evidence.

    UK

    Interestingly, it seems Sanofi had continue to supply Sanofi Connaught strain BGC in UK till July, 2019 .    UK seems to have chosen not to import other BCGS but rather apply dose reduction not by dividing the full dose into 1/2 or 1/3 as the US has done, but rather reducing number of doses according to risk stratification and according to the severity of shortage.  For example, if the supply is normal, a) for TaHG, give induction BCG and up to 2nd  3 weeks maintenance BCG, b) if supply is unavailable offer (assisted) intravesical mitomycin C chemotherapy +/- maintenance treatment.  But inform the patient mitomycin C chemotherapy reduces the risk of disease recurrence but not progression.     The detail of the risk stratification is described at the bottom of this posting.

    Also. British Association of Urological Surgeons acknowledges that the BCG shortage will be resolved in 2025 when MERCK expands the production capacity.

    The Department of Health and Social Care (DHSC) Medicines Supply Team have been working with MERCK to ensure that the limited supplies that will be made available in the UK are distributed equitably to hospitals.  Currently 90% caps on supplies are being implemented by wholesalers. The health service is likely to remain vulnerable to fluctuations in supply and it is anticipated that this fragile supply situation will exist until 2025 by which time expanded manufacturing capacity will be available.  OncoTice BCG® is the only licensed BCG bladder instillation product in the UK.  Although other strains of BCG are in use throughout the world, they are not licensed in the UK.

    Australia 

    It seems that from early stage of the BCG shortage both Australia and New Zealand  utilized the special provision  that will allow importing unlicensed medicines in case of acute shortage.  Canada has a similar provision but had  chosen not to exercise it.    The provision in Australia is Section 19A  of Therapeutic Goods Act.   In 2019, under Section 19A,   MEDAC (Germany) RIVM strain BCG became Authorized to be imported to Australia. Later, AJ Vaccine Danish strain BCG 30mg/vial became authorized to be imported by Section 19A.

    New Zealand 

    New Zealand has Section 29 which is similar to Section 19A in Australia, which will allow to import alternative medicines when it becomes acutely an available.   It seems that as Early as 2015,  New Zealand utilized Section 29 to import different BCG to deal with the shortage of MERCK Tice strain BCG.   The record shows that on MERCK Australia sent healthcare professionals Update on Supply Constraints – ONCOTICE (BCG Vaccine 500MCFU) and Availability of SII-ONCO BCG (40 mg/ml, 1 – 19.2 x 108 CFU) stating as follows.  Note I believe SII-ONCO BCG (40mg) is what VERITY Pharmaceutical markets in Canada as VERITY-BCG.

    Te Arai BioFarma has secured supplies of SII-ONCO BCG. SII-ONCO BCG will be available for order from Te Arai BioFarma as of Monday February 2nd. This product is not currently registered in New
    Zealand so will therefore have to be prescribed under section 29. Note also that the dosage and administration of SII-ONCO BCG is not the same as for ONCOTICE: 3 vials of SII-ONCO-BCG is to be
    reconstituted for administration.   Note that the full dose of SII-ONCO-BCG is 3 vials which is 120mg.  Also note that in Canada, the fuld dose of  VERITY-BCG (SII-ONCO-BCG) is 2 vials which is 80 80mg.

    New Zealand seems to be the country who has the longest experience to use SII-ONCO-BCG Russian strain and  MERCK Tice strain BCG.  So,  Canada can learn from their experience what will be the impact of using SII-ONCO-BCG Russian strain.  The study published by a hospital in New Zealand which says “Due to he global shortage of OncoTICE(Merck, USA) we utilized SII Onco BCG (Serum Institute, India).  However, we noticed higher discontinuation rates and severe complications in our patients with the use of SII Onco-BCG, one of them described with our case below.”    I interpret it as more patients who were using SII Onco-BCG Russian strain  had to stop BCG therapy due to its side effects than those patients who were on MERCK Tice strain BCG.   I sort of can understand the cause.  Granted that urologists are saying that different BCG strains should perform about the same, The full dose of MERCK Onco-Tice Tice strain is  50mg and the full dose of SII Onco-BCG Russian strain 40 mg x 3 = 120mg, which is 2.4 times of MERCK Tice strain full dose.   Notice in Canada, the full dose of Veirty-BCG Russian strain which is SII-Onco Russian strain BCG is 2 vials of 40mg each, which is 80mg.  So, I expect the severity of  side effect should be less that what the patients experienced with 120mg of SII-Onco-BCG Russian strain in New Zealand.

    Spain

    Spain was affected first by the BCG shortage caused by Sanofi.    Spain opted to allow importing of  BCG-Medac RIVM strain BCG 1 vial from Germany and  BCG-Culture Danish strain BCG  from Denmark (AJ vaccine) with 4 vials of 30mg each.     In this case,  the full dose of BCG-Medac RIVM strain BCG is 50mg 1 vial and the full dose of BCG-Culture  Danish strain BCG is 4 vials of 30mg or 12omg.

    It is interesting see that in the Spanish new media CONSALUD.ES article in 2017, Spain is thinking of having its own BCG. “AEU is working with a laboratory and possibly at the beginning of the year we will start a clinical trial with another type of BCG. ** Google Translate

    France

    Sanofi Connaught strain BCG was available till July 2019 in France.    France was importing MERCK OncoTice Tice strain BCG also till their supply became unavailable.   France also opted to allow importing of BCG-Medac RIVM strain BCG 1 vial from Germany and  BCG-Culture Danish strain BCG  from Denmark (AJ vaccine).   8,000 vials of BCG Medac were used every month but only 700 vials were available in January 2021 according to the Medicines Agency (ANSM). On June 16, The National Medicines Safety Agency (ANSM) announced BCG-Culture Danish strain BCG  from Denmark (AJ vaccine)

    Italy

    Italy has been importing BCG-Medac RIVM strain BCG 1 vial from Germany since the shortage began.   But, The shortage started April, 2019 as Medac in Germany had production problems.  The Medac owner announced on June 26, 2020 that the BCG will be available albeit with quantities, and therefore in quota distribution.  Oncotice, the therapeutic alternative, “has been lacking since January 30, 2020; supplies are expected for this medicine in July, which presumably will not allow the end of the shortage.   Consequently, the AIFA ( Italian Medicines Agency – Agenzia Italiana del Farmaco) released to health facilities (hospitals and ASL) which they apply for “authorization to import a similar product from abroad”.

    The lesson from  Italy that we still can have BCG shortage in Canada even if VERITY now supplies SII-ONCO-BCG Russian strain, especially VERITY-BCG can partially fills the shortage for TaHG and T1HG but not for CIS.  Also in order for VERITY-BCG to stay in the Canadian market, VERITY must complete the clinical trial with 518 patients at multiple centers within a reasonable time frame.

     

    Brazil

    I recall vividly that about 3 years ago in this discussion forum, a brother of a bladder cancer patients  in Brazil was desperately looking for BCGs to buy in Canada and send it to Brazil.  We found out that BCG for bladder cancer became unavailable and Brazil allowed BCGs to be imported.  The problem was that the shipping cost, customs process fee added to the price of BCG, and the cost reached near $1,000 per vial.  That was too much for general public in Brazil.  We were relieved to hear that his sister started receiving intravesical chemotherapy. A 2021 study paper says that  during the frequent periods of BCG shortage in the last four years, the only alternative is to directly import, at prices as high as US$ 5,000.00/12 vials (SWOG induction protocol) (26), instead of US$ 720.00. Additionally, the government does not acquire the onco-BCG directly from FAP anymore, and each hospital has to buy its supply through independent distributors. Right now, most patients are not receiving BCG treatment (or any treatment), and many patients are progressing to invasive disease and dying of BC much more than they should.

    There is only one producer of BCG in Brazil.  Ataulpho de Paiva Foundation (FAP) started BCG vaccine production for tuberculosis in 1934 for BCG.  The BCG strain is Monreau.  One of the products that FAP produces is ImunoBCG for Bladder Cancer, this product has been on the market since 2005.   FAP is not a private company.   120,000 doses of ImunoBCG have been manufactured in 2020.

    The same study paper says that there is a technology transfer agreement between FAP, in Brazil, and a Spanish institution, with a new manufacturing center being developed in Madrid to supply the European BCG market.  This news matches the comment made by a Spanish authority that Spain in working on developing their own BCG.

    UAE – United Arab Emirates

    UAE is an oil rich country.  I do not have much access to their news if there is a BCG shortage or not.  But I have found out from another discussion form that in UAE, two BCGs have been available in UAE.  One is Medac-BCG RIVM strain from Germany and SII-ONCO-BCG Russian strain from India.  In UAE, there are financially well off people and there are the opposite, mostly consisting of seasonal immigrants from overseas on low paying jobs.  Medac-BCG costs 183 Euro in Italy, so I would assume the similar price in UAE.  SII-ONCO-BCG costs 780 Indian Rupees which is about $13.  I can guess who buys which BCG in UAE.  Still,  I am relieved to know that SII-Onco-BCG is being supplied in UAE so bladder cancer patients with low income get treated with BCG.

    ASIA  

    I have not checked much, but I have not heard of the BCG shortage in Japan, Korea or Taiwan. I will see if I can find it more in this region

    Other countries

    I have not checked much.

    Many countries with lower GDP are receiving BCGs at lower cost from  low cost suppliers because of lower wage such as SII or Green Signal Biopharm in India. SII is the major suppliers to countries with lower GDP. The list of countries SII and Green Signal ship their Russian strain BCG and Danish strain BCGs are listed in the previous posting.   Note that SII is a largest (in volume) vaccine manufacturer in the world.  SII invested (gambled) in building manufacturing farcicalities for Astrazeneca-Oxford Covid-19, which incidentally was sold in Canada under the name of COVID-Shield.  So, I believe that SII has technology and experience to produce quality BCG. Their providing BCG at lower cost than  the price of BCG what the companies operating in higher wage countries produce are definitely enabling bladder cancer patients in those countries to receive BCG treatment for bladder cancer.

     

    AUA Guidelines for the treatment for non-muscle invasive bladder cancer.

    Until the shortage has been resolved, the following strategies may help maximize the care for patients with Non-Muscle Invasive Bladder Cancer (NMIBC), subject, as always, to physician judgment in individual cases:

    – BCG should not be used for patients with low-risk disease.
    – Intravesical chemotherapy should be used as the first-line option for patients with intermediate-risk NMIBC.  Patients with recurrent/multifocal low-grade Ta lesions who require intravesical therapy should receive intravesical chemotherapy such as mitomycin, gemcitabine, epirubicin or docetaxel instead of BCG. If BCG would be administered as second-line therapy for patients with intermediate-risk NMIBC, an alternative intravesical chemotherapy should be used rather than BCG in the setting of this BCG shortage.

    -For patients with high-risk NMIBC, high-grade T1 and CIS patients receiving induction therapy, they should be prioritized for use of full-strength BCG. If not available, these patients and other high-risk patients should be given a reduced 1/2 to 1/3 dose, if feasible. If supply exists for maintenance therapy for patients with NMIBC, every attempt should be made to use 1/3 dose BCG and limit dose to one year.
    In the event of BCG supply shortage, maintenance therapy should not be given and BCG-naïve patients with high-risk disease should be prioritized for induction BCG.
    If BCG is not available, a preferable alternative to BCG is mitomycin (induction and monthly maintenance up to one year). Other options such as gemcitabine, epirubicin, docetaxel, valrubicin or sequential gemcitabine/docetaxel or gemcitabine/mitomycin may also be considered with an induction and possible maintenance regimen.
    Patients with high-risk features (i.e., high-grade T1 with additional risk factors such as concomitant carcinoma in situ, lymphovascular invasion, prostatic urethral involvement or variant histology) who are not willing to take any potential oncologic risks with alternative intravesical agents, should be offered initial radical cystectomy, if they are surgical candidates.
    ADDITIONAL NOTES:

    If 1/2 to 1/3 dose BCG is used, every attempt should be made to treat multiple patients on the same day, while being consistent with product labeling, to avoid drug wastage. It is recommended practitioners communicate with their pharmacy to ensure that if split dosing is used, it is done with appropriate safety precautions.

     

    UK risk stratification based upon the availability

    SCENARIO A – STANDARD HRNMIBC (G3pTa alone)   *Gp3Ta is  TaHG

    Routine supply
    give induction BCG and up to 2nd batch of 3 doses of maintenance BCG
    Limited supply
    give induction BCG and up to 2nd batch of 3 doses of maintenance BCG, if available, if 2nd batch of 3 doses of maintenance BCG not available, consider intravesical mitomycin C chemotherapy (assisted with hyperthermia or electromotive delivery if locally available) Ref 3.
    Supply unavailable
    offer (assisted) intravesical mitomycin C chemotherapy +/- maintenance treatment * (see below)
    * Patients receiving (assisted) mitomycin C chemotherapy should be counselled that treatment reduces the risk of disease recurrence but not progression

    SCENARIO B – VERY HRNMIBC (G3pT1 +/- pTis)   * G3 is HG  pTis is CIS

    Routine supply
    give induction BCG and up to 8th batch of 3 doses of maintenance BCG
    Limited supply
    give induction BCG up to 2nd batch of 3 doses of maintenance BCG.  Patients who have reached years 2 and 3 of maintenance should be counselled that this is safe in terms of progression Ref 4, although there is a slightly higher risk of recurrence in the very highest risk HRNMIBC patients; or excluding patients with pTis, following induction and up to 2nd barch of 3 doses of maintenance BCG therapy, offer (assisted) mitomycin C chemotherapy, or alternative maintenance intravesical chemotherapy (e.g. epirubicin); or consider induction treatment with intravesical gemcitabine chemotherapy Ref 5.
    Supply unavailable
    excluding patients with pTis, consider induction & maintenance therapy with (assisted) mitomycin C chemotherapy; or consider induction treatment with intravesical gemcitabine chemotherapy ** (see below)
    ** Patients receiving alternative chemotherapy should be counselled that treatment reduces the risk of disease recurrence but not progression

     

    • This reply was modified 2 years, 11 months ago by Joe.
    #42764
    Joe
    Participant

    Learning from BCG shortage for BCG vaccine and how WHO try to mitigate the risk of the shortage

    BCG was developed early 1900 to prevent tuberculosis (TB). Wikipedia says in the 18th and 19th century in Western Europe, TB had a mortality rate as high as 900 death per 100,000 per year.  A 2017 study by UK, USA and WHO estimated that 239,000 children younger than 15 years died from tuberculosis worldwide in 2015;80% of these deaths were children younger than 5 years.    Many children death by TB are born in poor countries.   According to HO 300 millions doses are administered to infants and children around the world according to WHO, and more than 100 million newborns around the world receive BCG vaccination.  This is the reason why WHO includes BCG vaccine  in its essential medicine.

    UNISEF buys 50% or 150 million doses of BCG vaccine from prequalified BCG manufactures on be half of 70 countries.    There are 5  WHO prequalified BCG manufacturers, and they are are Japan BCG Laboratory in Japan (Tokyo-172 strain),  Serum Institute of India (SII) in India (Russian strain), AJ Vaccine in Denmark (Danish strain), BulBio-NCIPD in Bulgaria (Bulgarian strain), and Green Signal Biopharm in India (Danish strain).   Note that Green Signal Biopharm was delisted in October, 2019 from prequalified supplier due because the company failed to meet WHO Prequalification Inspection.    There are 14 other BCG vaccine manufacturers in the word.

    Notice Japan BCG Lab in Japan, AJ Vaccine in Denmark, SII in India, Green Signal Bio in India sell BCG for bladder cancer also.  It is reminded that those manufactures have a single production line which produces BCG for vaccine and BCG for bladder cancer though the final package processes are different.    Also put it in perspective, one vial of SII-Onco-BCG (40mg) which VERITY sells in Canada as VERITY-BCG  is equal to 4,000 doses of BCG vaccine for new borns according to SII presentation.  Because the full dose of VERITY-BCG for bladder cancer is 80mg, it is equivalent of 8,000 doses of BCG vaccine for new born.  It is something we should be cognizant about the fact that bladder cancer patients are sharing the same BCG resources with infants around the world to prevent them from tuberculosis.

    BCG vaccine shortage happens

    The Lancet which is one of the most respected peer reviewed general medical journal published in January, 2019  an article “Global shortage of BCG vaccine and tubeculosis meningitis in Children”.

    Due to problems with vaccine production and limited supplier options in some countries, the global availability and procurement of BCG has been a challenge since 2013.  Concern was expressed in 2016 that this could lead to substantial increases in child mortality globally. A mathematical model estimated that, globally, more than 100 000 deaths per birth cohort over the first 15 years of life could result from interrupted BCG vaccine supply. To date, there have not been any empirical data to document the actual consequences of BCG shortages.   The study showed a sharp increase in number of admissions for tubeculous  meningitis of tubeculomas < 2 years of age from 2013 to 2015 in South Africa.  Disruptions to vaccine supply can have multiple effects on the health system delivery of BCG. Strategies should be put in place to prevent such stockouts. Given the paucity of current tools to combat this devastating form of tuberculosis in children, we, as a global community, must demand that supplies and quality of BCG vaccine remain secure.     Notice that WHO has managed BCG vaccination program over 100 years since The League of Nations, the predecessor of United Nation stared BCG vaccination program in 1927.   100 years later, still BCG vaccine shortage happens.  It is a reminder to us that challenges to eliminate the shortage in any commodity including BCG for bladder cancer.

    How WHO manages the risk of BCG vaccine shortage.

    WHO needs to manage the cost and the supply.    WHO has now 4 prequalified BCG vaccine suppliers as Green Signal Bio in India was delisted because of quality control issue.  of which 3 of them also sells BCG for bladder cancer.   WHO buys 50% of BCG vaccine supplies from the two prequalified suppliers.  The rest come from other prequalified suppliers and 15 non prequalified suppliers.   WHO controls the cost/pricing by some from high price BCG suppliers such as Japan BCG Lab in Japan and AJ vaccine in Denmark and low price BCG supplier such as SII in India and Bul-Bio in Bulgaria.   Still, there are fluctuations in supplies ,eg.  Green Signal Bio in India was supplying 30% of WHO demand, and after their delisting from prequalified suppliers, WHO has to look for other suppliers to fill the hole.   Also, even prequalified suppliers suddenly stops delivering their BCG because of the maintenance & upgrading the production facilities and product quality issue because BCG is live bacteria.   So, now WHO orders  BCG vaccine according to expected demand plus surplus.

    In summary,  WHO manages the risks of BCG vaccine shortage by

    – having multiple (currently 4)  prequalified  suppliers

    – buying surplus over the forecasted demand

    – having non-prequalified suppliers around the world, many of which supply BCG vaccine to own countries.

    WHO manages the quality of BCG vaccine by

    – Providing the qualify control method to all BCG  manufacturers

    – Regulating tight control on product quality  to prequalified suppliers.  One such quality control is viability of number of bacteria counts (CFU) to be within 4 folds as it affects efficacy of the vaccine

    WHO manages the cost/budget for BCG vaccine by

    –  mixing  BCG vaccine suppliers with higher cost production suppliers, i.e. Japan BCG Lab in Japan, AJ Vaccine in Denmark  and lower cost production suppliers such SII in India and Bul-Bio in Bulgaria.

     

    This is the last but one posting on this subject.

     

     

    #42783
    Joe
    Participant

    BCG business and Pharmaceutical industry

    I do not know the past, but now BCG vaccine business and BCG for bladder cancer business are like a speckle  compared to the total business for large pharmaceutical companies.  BCG was developed 100 years ago, so there not are good wills like patent which can keep the price of BCG high.  The BCG manufacturing process for BCG is well established, since freeze drying process was implemented in 1960s, no major advancement was made in BCG manufacturing process.  Basically, BCG vaccine and BCG for bladder cancers are low value added product which cannot make much profit unless they are produced in countries with lower wages.  So, many growth focused large pharmaceutical companies left BCG business including Sanofi.    I wanted to look at this issue objectively by looking at the data.

    BCG vaccine business

    According WHO,  the world BCG market size is  300M doses and the cost is US$ 60M.  Its breakdown by income based countries are shown below.

    – $10M in high income countries

    -$25M  in upper middle income countries

    -$2M in lower middle income countries

    -$6M in low income countries

    The price is what UNESCO pays in US$ per dose to prequalified suppliers are listed below.  Note UNESCO buys 50% or 150M doses and distribute to poor countries.

    2004       2016         2019        2021

    Green Signal Bio (India)                       0.068        0.105

    Intervac (Canada)                 0.05         0.08

    Japan BCG Lab(Japan)       0.09         0.162                       0.1870

    SII  (India)                             0.051       0.105                       0.1205

    AJ Vaccine                                                               0.2625    0.2760

    BULBIO  (Bulgaria)                                               0.09        0.1005

    WHO says UNESCO buys 75% of  BCG from two prequalified manufacturers, which I believe they are Japan BCG lab (JBL) and SII.  Assuming Japan BCG Lab and SII 50% each to UNESCO.  Revenue from their BCG vaccine business can be estimated as ( 300M doses x 50% x 75% / 2) x price of BCG.    Total vaccine business in doses is 56.25 million doses each for JBL and SII.  The revenue for JBL is $10.5M, and $6.8M for SII.    Also, 25 million children are born in India.  There are four BCG vaccine manufacturers in India, SII and  Green Signal Bio, Taj Pharm. BCG Vaccine Lab who share the BCG vaccine market in India.   Revenue may not be much as the government cap the price of BCG vaccine according to Green Signal Bio.   Green Signal Bio business consists of BCG vaccine and BCG for Bladder Cancer, they depend on foreign business for its growth.    So, I estimate BCG vaccine business for SII is a about US$10M.

    Company size comparison

    MERCK  USA                                  Asset  US$90B            Revenue  US$ 49B (2021)                   74,000 employees

    SII (private company) India       Asset  unknown           Revenue US$ 800M (2019-2020)     1140 employees

    Medac Germany                           Asset   US$400M         Revenue  US $550M (2018-2019)     1,220 employees

    AJ Vaccine  – Denmark               Asset   US$250M          Revenue   US $52M  (2020)                  600  employees

    Japan BCG Lab – Japan             Asset    US$140M          Revenue   US $20-$50M                         275  employees

    VERITY Pharma Canada          Asset ?                             Revenue                                                        ?     employees

    **  VERITY Pharmaceutical was established in 2016 in Canada and imports SII Russian strain ONCO-BCG and market as VERITY-BCG.  VERITY Pharmaceutical also marketed AstraZeneca-Oxford Covid-19 vaccine which was manufactured by SII in India  under the brand name of COVID-Shield

     

    BCG for Bladder Cancer Business

    BCG business and Pharmaceutical industry

    Because BCG which is used for BCG vaccine and BCG for bladder cancer are produced in the same manufacturing process.  Though MERCK produces BCG only for bladder cancer, other manufacturers use the same production line for BCG vaccine and BCG for bladder cancer except for packaging process.  Also, most BCG manufacturers have a single BCG production line.   So, it is important to look at BCG for bladder cancer business in conjunction with BCG vaccine business.

    BCG vaccine business

    According WHO,  the world BCG market size is  300M doses and the cost is US$ 60M.  Its breakdown by income based countries are shown below.

    – $10M in high income countries

    -$25M  in upper middle income countries

    -$2M in lower middle income countries

    -$6M in low income countries

    The price is what UNESCO pays in US$ per dose to prequalified suppliers are listed below.  Note UNESCO buys 50% or 150M doses and distribute to poor countries.

    2004       2016         2019        2021

    Green Signal Bio (India)                       0.068        0.105

    Intervac (Canada)                 0.05         0.08

    Japan BCG Lab(Japan)       0.09         0.162                       0.1870

    SII  (India)                             0.051       0.105                       0.1205

    AJ Vaccine                                                               0.2625    0.2760

    BULBIO  (Bulgaria)                                               0.09        0.1005

    WHO says UNESCO buys 75% of  BCG from two prequalified manufacturers, which I believe they are Japan BCG lab (JBL) and SII.  Assuming Japan BCG Lab and SII 50% each to UNESCO.  Revenue from their BCG vaccine business can be estimated as ( 300M doses x 50% x 75% / 2) x price of BCG.    Total vaccine business in doses is 56.25 million doses each for JBL and SII.  The revenue for JBL is $10.5M, and $6.8M for SII.    Also, 25 million children are born in India.  There are four BCG vaccine manufacturers in India, SII and  Green Signal Bio, Taj Pharm. BCG Vaccine Lab who share the BCG vaccine market in India.   Revenue may not be much as the government cap the price of BCG vaccine according to Green Signal Bio.   Green Signal Bio business consists of BCG vaccine and BCG for Bladder Cancer, they depend on foreign business for its growth.    So, I estimate BCG vaccine business for SII is a about US$10M.

    Estimated revenue from BCG Vaccine Business

    Japan BCG Lab  US $10M

    SII – India  US$10M

    Green Signal Bio – India 0.3M US$ 2016  for BCG vaccine + BCG for bladder cancer

    MERCK USA  None

     

    Company size comparison

    MERCK  USA                                  Asset  US$90B            Revenue  US$ 49B (2021)                   74,000 employees   Founded in 1891

    SII (private company) India       Asset  unknown           Revenue US$ 800M (2019-2020)     1140 employees        Founded in 1966

    Medac Germany                           Asset   US$400M         Revenue  US $550M (2018-2019)     1,220 employees      Founded in 1970

    AJ Vaccine  – Denmark               Asset   US$250M          Revenue   US $52M  (2020)                  600  employees    In 2017, AJ Vaccine acquired Danish government run SII, which was founded in 1902

    Japan BCG Lab – Japan             Asset    US$140M          Revenue   US $20-$50M                         275  employees    Founded in 1952

    Green Signal Bio – India            Asset   small                   Revenue   US $5M                                   < 100  employees  Founded in 2005

    VERITY Pharma Canada          Asset ?                             Revenue                                                        ?     employees     Founded in 2016

    **  VERITY Pharmaceutical was established in 2016 in Canada and imports SII Russian strain ONCO-BCG and market as VERITY-BCG.  VERITY Pharmaceutical also marketed Atrazenia-Oxford Covid-19 vaccine which was manufactured by SII in India  under the brand name of COVID-Shield

     

    BCG for Bladder Cancer Business

    There no easily available hard data about the market size of BCG for bladder cancers on internet, so I have relied bits and pieces of information available in terms of pricing, the volume to come up with estimate the best I can.

    1.   Sanofi and Merck were dominant suppliers in NA and in Europe suppliers their BCG for bladder cancer, mainly to high income countries.

    2.  Merck produces about 1 M doses a year

    3.  Merck sells its Onco-Tice BCG at the average price of $150 per vial

    4.  SII in India ships their ONCO-BCG Russian strain to 21 countries – mostly lower middle income and lower income countries

    Price of SII ONCO-BCG is about 750 Indian Rupees, which is US$10 per vial whole sale price.

    Note that SII-ONCO-BCG  is sold at $176 for 120 mg (40mg/vial x 3) in New Zealand vs MERCK Onco-Tice (50mg) vial x 1 for $150.

    5.  Green Signal Bio in India ships their UROVAC Danish strain to a few lower income countries.

    6.  Japan BCG Lab sells their Immunobladder Tokyo-172 strain BCG to only in Japan and neighboring countries such as Korea, Taiwan

    The price of immunobladder is US$140 for 80mg vial and US$70 for 40mg vial

    7. Medac in German produces its own BCG-MEDAC RIVM strain BCG for bladder cancer in Germany

    The price of BCG-MEDAC is 170 Euro per 50mg vial

    8.  AJ Vaccine in Denmark produces its own CultureBCG Danish strain  for bladder cancer in Denmark

    The price of AJ Vaccine is similar to  BCG-MEDAC.

    9.  FAP in Brazil produces its own Monreau strain BCG for bladder cancer in Brazil

    The price of FAP Monreau strain BCG is US$65per 40mg vial.

     

    Estimated number of vials sold in a year

    There are no data publicly available to show  how many vials are used a year in each country.   But there was an article by French news paper Le Parisien on January, 2020 states that when MERCK ONCO-TICE BCG became un available, 8,000 BCG-MEDAC vials were used monthly.   Using this data and the population in France which is 65 million,  The estimated consumption of BCG vials / per person was calculated as 8,000/65 million = 0.00012 vial per person in a year.   This number was applied to every country in the world to estimate the consumption of vials for each country per year.    US$150 was applied to European countries except Russia as they probably produce their own.   Accordingly the total estimated annual consumption of BCG for bladder cancer  became in Europe  860,000 vials and in NA 420,000 vial.  The cost for Europe and NA became US$ 170 million.  Except  Japan and neighboring high income countries,  the total cost for remaining countries should be small as the price ($US 10-15 per vial) of SII and Green Signal per vial is almost 10 fold  cheaper than MERCK Onco-TIce BCG which is  US$150 per vial.

    Accordingly, rough estimated total global business of BCG for bladder cancer is US$200M-$230M.

    This amount is too small for large pharmaceutical companies like MERCK and Sanofi.  The annual revenue of MERCK is US$49B.  The annual revenue of Sanofi is US$ 40B.   US$200M BCG business is less than 0.5% of their total business, and BCG business is not profitable business for those pharmaceutical companies.    Financially, BCG business is not attractive business for pharmaceutical companies unless they are low cost overseas producers.  But because BCG is such a crucial drug for high risk non muscle invasive drug, we would like to see the manufacturing facility run by financially sufficiently stable company with competent technical capability be physically us, preferably in Canada.  Sanofi BCG fab in Ontario was such a company.  Financially, it made a sense for Sanofi to exist BCG business.   But, I believe there is implicit contract which is social responsibility to those patients who are paying directly or indirectly to those pharmaceutical companies expecting the company would continue to provide the drug, especially when comparable alternatives are not readily available without lengthy clinical trials.  In this sense I think Sanofi did not fulfil the contract.  Even in professional sports, when you have 50 million dollars 4 years contract and the team wants to get rid of the player in the middle of the contract, for example after 2 years, and the team will trade the player to another team and the other team agrees to take the payer for $3M per year, the team who is trading the player has to pay the difference to the other team, so the player will be getting what the original contract promised.   So, Sanofi could have paid $100-200M to potential buyers for their BCG business so Sanofi could honor the social responsibility contract which Sanofi had made implicitly with bladder cancer patients in the world.    I do not think companies  with implicit social responsibility, pharmaceutical companies especially patients suffer when they stop producing the dug when patients life depend upon it whether the product becomes less profitable or not, especially the additional investment to upgrade the fab or even build a new fab would not have impacted much financially for large pharmaceutical companies like Sanofi.  So, I am extremely unhappy to exist the BCG business knowing the chaos it would cause. Also, I am not happy with the fact that the Canadian government did not step in to stop Sanofi to leave the BCG business from Canada.    After all Canada was the country of invention of BCG for bladder cancers by Dr. Alvaro Morales of Queens University and Canada even introduced two different BCGs with Connaught strain and with Flappier strain into the market.

     

     

     

     

    #42785
    Joe
    Participant

    Summary,

    Most countries in Europe have used  special provision to allow BCG with different strains following Sanofi stopped supplying Connaught strain BCG in Juley 2019, for example, Europe countries started importing BCG-MEDAC with RIVM strain from Germany and Culture-BCG from AJ Vaccine in Denmark.  Still, they experienced shortage sometimes with the shortage of BCG-MEDAC and Culture-BCG.   Spain is thinking of building its own BCG production facility in Spain working with FAP lab in Brazil with Morneau strain.

    Australia and New Zealand seemed to use their special provision as early as 2016 and allowed importing other BCGs to offset the shortage of MERCK ONCO-TICE BCG

    UK decided not to import other BCGs but dealt with the shortage of MERCK Onco-Tice by stratifying the patients risk and modify the length of BCG treatment but still with  full dose. Meanwhile MERCK seemed to offer their commitment to meet 90% of usual demand as long as MERCK is sole supplier.

    The US decided not to import other BCGs but dealt with the shortage of MERCK Onco-Tice by stratifying the patients risk and reducing the dosage to 1/2, 1/3 of BCG treatment.  Meanwhile US started SWOG-1602 to compare if Tokyo-172 strain BCG is not inferior to MERCK Onco-Tice BCG. SWOG_1602 PHASE 3 completed and waiting for the result of the trial.

    MERCK had announced the construction of additional manufacturing line to triple volume of Onco-BCG production by 2015-2026

    Asia did not seem to have experienced the shortage – Japan, Korea, Taiwan.    I am waiting a reply regarding  if the shortage had happened in China.

    Health Canada approval to Verity Pharmaceutical for TaHG and T1HG but not for CIS on condition that VERITY Pharmaceutical complete the clinical trial involving 518 patients to show VERITY-BCG, which is equivalent of SII Onco-BCG, is not inferior to MERCK Once-Tice BCG in a reasonable time frame.  I think the investment& time required to complete the clinical trial is the main hurdle.

    Other low income countries –  I had not  thought of what’s happening to bladder cancer patients in low income countries, if there are bladder cancer patient there or what kind of treatments they are receiving, including BCG treatment.    Maybe WHO should consolidate BCG for bladder cancer from different suppliers and distribute to different countries just like they are doing for BCG vaccine.

    BCG is generic drug with low profit to most pharmaceutical companies.   Kenneth Frazier, the chairman and former CEO of MERCK, told in a interview in 2019 about MERCK’s Onco-Tice BCG business, that   this is an exemplar of a big problem that is going to continue to be here for us going forward when the prices of drugs get too low particularly drugs are generic drugs then you don’t have market incentive for people to put the capital up to build facilities like we need for additional amounts of this BCG drug.  He concluded by saying that  the moral of the story is sometimes drugs are not available because the prices are too low not because the prices are too high.  Anyway, two years later, Merck had decided to build a new facility to triple the  production volume.   So, the shortage has changed from the permanent problem to a temporary problem for MERCK Onco-Tice BCG users.

    Incidentally Sanofi was making a major change and restructured the company around 2016. Before the change, Merck and Sanofi had a joint marketing agreement which had lasted 22 years  that MERCK  markets Sanofi vaccine products  in North America and Sanofi markets MERCK’s vaccine products in Europe.   In 2015, two companies generated $908 million dollars revenue which was split 50/50 between two companies.   This joint venture was dismantled in March 8, 2016.  In November in the same year, Sanofi announced the abandonment of their BCG business.   So, the restructuring of Sanofi might have contributed more to the exit from BCG business and the closure of the production facility in Ontario rather than the production quality control issue.   Interesting!!

    That is all

    best

     

    #42786
    Joe
    Participant

    I just got a reply from China.  China National Biotec Group manufactures BCG for Bladder cancer, and there are no shortage in China.

     

    #42928
    Tana
    Participant

    Hi Joe- that is an amazing amount of research you have posted.
    My view is I’m grateful that we Canadians are given BCG free to stop our bladder cancer. I have no idea of any research or what type BCG  I am given.
    I have simply put my trust in the Medical Services Plan of BC with gratitude to receive it.
    Thanks Joe for your research.

    #42985
    Joe
    Participant

    Hi Tara,

    You have been treated with ONCO-TICE ® TICE strain BCG, which is manufactured and marketed by MERCK in the production line in Durham, North Carolina.   For each BCG treatment, 100 to 800 million colonies of BCG bacteria are instilled into your bladder.

    BC Cancer Agency updated in February, 2020 the protocol of BCG for instillation as follows

    “Until recently, Tice BCG (OncoTICE) has been the only BCG strain available in Canada. A second strain of BCG, Russian BCG-I (VERITY-BCG), received conditional Health Canada approval last year. To improve the availability of BCG during times of drug shortage, BC Cancer is adding VERITY-BCG to the Benefit Drug List as of 01 February 2022, as an alternate to the current OncoTICE brand. Note that OncoTICE should continue as the default brand and that VERITY-BCG is to be used when OncoTICE is not available.”

    So, you will be receiving the same Onco-Tice ® strain BCG in full dose until the completion of your BCG treatment as long as Merck Onco-Tice ® strain BCG remains available at the time of your remaining BCG treatments.

    BC Cancer Agency – Update on BCG for bladder cancer

    http://www.bccancer.bc.ca/systemic-therapy-site/Documents/2022%20ST%20Updates/ST%20Update_Feb%202022.pdf

    BCG for bladder cancer is a miracle drug because  it has been the most effective drug to treat intermediate and high risk non-muscle invasive bladder cancer over 40 years since our Canadian urologist Dr. Alvaro Morales of Queens university had proved its effectiveness, and  it is very inexpensive – an average whole price for $180-$190  per 1 5omg vial according to Mayo Clinic.    So, the cost of the entire 3 years treatment  or  24  treatments  of  BCG is less than $5,000.   $5,000 for the entire 3 years BC treatment is very low compare to the price of new bladder cancer drugs for BCG unresponsive which Institute for Clinical and Economic Review recommending  $100,000 to $200,000 per year.    So, I do not think the cost of BCG is not that much burden to our healthcare system comparing to other cancer treatment.  I think one of core causes of the  shortage of  inexpensive drugs including BCG is that though the government/ Health Canada is very strict on the approval of a new drug, the government has no legal power to disapproval of any drug be withdrawn from the market.    A case in point is the recent announcement of withdraw of  Intron A (R) Inteferon alpha-2b by MERCK.    Intron A (R) Inteferon alpha-2b has been used for various cancers, including BCG unresponsive bladder cancers as BCG+Interferon alpha-2b.  There are no other manufacturers that produce interferon alfa-2b.  MERCK.   According to Optum, a healthcare service company, Intron A is being discontinued by Merck due to business reasons and is not due to any safety, efficacy
    or quality reasons.   The cost of Intron A was  US$ 330 according to Drug.com.  So, the  material cost for the BCG + Interferon alpha-2b for the treatment for BCG Unresponsive non-muscle bladder cancer was about $500.   I am aware of a few patients who had benefited from BCG + Interferon alpha-2b.   So, I am not happy that we are losing another inexpensive drug for non-muscle invasive bladder cancer.  Luckily, there are now a few alternative treatment for BCG unresponsive including Pembrolizumab (Keytruda) systemic treatment  by Merck which costs near $100K per year, which had been approved by FDA, but I do not think it had been approved by Health Canada, yet.   Luckily,  Intravesical chemotherapy Gemcitabine + Docetaxel which has shown good efficacy  is now  being offered to BCG unresponsive in VGH.   I wish that patients have a say to drug companies not to discontinue key drugs if it impacts patients significantly.

    best

     

     

     

    #43103
    Joe
    Participant

    Comparison of Efficacy between MERCK (USA)  TiCE strain BCG and MEDAC (Germany) RIVM stain BCG

    TICE strain BCG  2-8×10**8 CFU,   RIVM strain BCG  2×10**8 -3×10**9

    BCG seed TICE (OncoTICE®, MSD, NJ, USA; 2–8 × 108 CFU), and (2) BCG seed RIVM (Medac®, D-20354 Hamburg, Germany; 2 × 108–3 × 109 CFU).

    The result of the study was published in Februray, 2022,  which compared the efficacy and side effects of MERCK (USA)  TiCE strain BCG and MEDAC (Germany) RIVM stain BCG

    – The protocol  was 6 weeks induction treatment and 3 years of maintenance.

    – 719 patients had received RIVM strain and 133 had received TICE strain.

    – Ta 262 (30.7%), T1 590 (69.3%), LG 23(2.7%), HG 829 (97.3%),  CIS – concomitant 52 (6.1%)

    – Selected patients were treated at two large institutions in Italy.

    –  It was not RAMDOM test.  Allocation of each strain to each patient was caused by differences in supply and distribution. Allocation was not planned and randomized; the choice of BCG selection over the years was made based on competitive price as well as on the commitment by the manufacturing company to ensure a steady supply of the intravesical therapy.

    Results

    Side effects were similar

    5 years recurrence free survival rates were similar

    5 years progression free survival rates were similar

    In dealing with the future shortage, the study recommends large scale random clinical trial.   Nevertheless, this was relatively large study involving 719 patients.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8869903

    #43370
    Joe
    Participant

    Revision of BCG protocol by BC Cancer Agency

    I usually follow BC Cancer Agency for availability and protocol for bladder related treatment,   So, I have been following the BCG protocol since Verity-BCG (™) had received conditional approval by Health Canada.  On December 17, 2021 BCC made an announcement that the Medical Advisory Board of Bladder Cancer Canada, with endorsement by the Canadian Urological Association (2021), had reviewed and support the following suggestions.

    Every patient in need of BCG therapy should receive full dose BCG as per CUA guidelines(1).
    Patients with high risk NMIBC should receive full dose BCG for 6 weeks of induction and 3 years of maintenance therapy.
    When BCG is administered to patients with intermediate risk NMIBC, full dose BCG for 6 weeks of induction and 1 year of maintenance therapy is recommended.
    Patients should ideally receive all treatments with a single strain of BCG. However, if supply of one BCG strain is limited, patients should be switched to the other strain if necessary to ensure full dose BCG is administered for the recommended duration of maintenance therapy.
    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.

    Accordingly BC Cancer published the new BCG protocol  early January, 2022.   Below were main points related to the use of two different BCGs.

    • OncoTice should be used first when it is available
    • Verity-BCG is not approved for CIS.

    On May 12, 2022 BC Cancer published updated BCG protocol on May 22, 2022.    The content is quite different from the original BCG protocol

    ELIGIBILITY:  Urothelial carcinoma of the bladder

    Any of the following uses:  Carcinoma in situ (CIS) , Therapy of truly unresectable Ta (papillary urothelial carcinoma),   Prevention of recurrence/progression of resected T1 disease (superficial invasion of submucosa),    Prevention of recurrence/progression of resected high grade Ta  Prevention of recurrence of resected multifocal or recurrent or large (>3cm) low grade Ta tumour

    Note:  Brand selection based on product availability and physician’s discretion  etc.

    It no longer states that VERITY-BCG is not approved for CIS or OncoTice should be used first if availabe.   The document does not state the reasons for the update.

    It is confusing as there are no updates on the Health Canada site, BCC or Canadian Urological Association (CUA) on this matter. Health Canada still shows the conditional approval of Verity-BCG. The BCC and CUA site show the original consensus statement for the integration of Merck Onco-Tice BCG and Verity-BCG, which states Verity-BCG is for papillary type urothelial carcinoma but Verity-BCG is not approved for carcinoma-insitu (CIS) type.

    I liked the original version of the BCG protocol as physicians and patients who may read this BCG protocol which is accessible to public may interpret that Verity-BCG is approved also for CIS.   Also, I prefer that the decision of which brand to be used should not be left alone to physicians but rather patients should be able to participate in the decision after the physician explains about the shortage and the difference between two brands.

    In the BCC podcast on BCG, Dr. Alexander Zlotta of UT said BCG with different strains should give the similar result.  The main difference in the protocol for Verity-BCG and Merck Onco-Tice BCG is the amount of BCG bacteria administered in one treatment.

    For MERCK ONCO-TIce BCG, for a single treatment, 1-8×100**8 CFU numbers of BCG bacteria are administered.  For Verity-BCG, for single treatment, 2 times of 1-8×100** CFU numbers of BCG bacteria are administered.  This is because for MERCK BCG, 1 vial which contains 1-8×10**8 CFU is administered for a single treatment, but for Verity-BCG, 2 vials, each vial containing 1-8×100** CFU are administered for a single treatment.

    The product monogram of MERCK Onco-Tice BCG says each of their 50mg vial contains 1-8×10**8 CFU BCG bacteria.    The product monogram of Verity-BCG says each of their 40mg vial contains 1-8×10**8 CFU  BCG bacteria.

    Full dose for MERCK Onco-Tice BCG is a vial or 50mg.   Full dose for Verity-BCG is two vials of 40mg, which become 80mg.   So, patients who receive a full dose of Verity-BCG will receive twice as much BCG bacteria administered to the bladder compared to patients who receive a full dose of MERCK.

    You may question if a 40mg vial of Verity-BCG contains the same amount BCG in a 50mg vial of MERCK BCG, why don’t they just administer a 40mg vial of Verity-BCG as the full dose.  This is because Health Canada approves drug based upon clinical test data.  As I mentioned before Health Canada gave conditional approval because the clinical test data were not randomized test compared to MERCK onco-tice BCG, but rather on two clinical trials for Russian strain BCG alone  by SII in india for 80mg and 40mg. Also, all SII BCG customers are receiving in 40 mg vials, and production line has been producing 40 mg vials only for  many years for bladder cancer, so it is financially prohibitive to modify the production line to enable to produce 50mg vial just for Verity-BGC

    best

    #43371
    Tana
    Participant

    Hi Joe- thanks- I find this very interesting and incidentally timely that I received this today just when I was wanting to know more about BCG strengths yesterday as I was asking my bb ( bladder buddy if I could quit!).
    I am close to the finish line yet I want to quit. I get so sick with it and I wanted to ask is there a way of reducing the strength? So reading this info now makes me curious what I am being given- is it protocol all nmibc  ( I am ta high grade) gets the same one strain- one vial Merck is it? – over three years? I have not talked to my doctor except after last cysto when he said I must be excited I only have two more sets to go. I had asked him after the biopsy about the inflammation and red spot which he called it some name- bladder ititis – but wanted me to continue bcg even though I said it’s too strong for me- he comments that this is looking after me! So I guess it is a small price to pay As it is working to keep me clear ( though I always wonder if I’d be clear anyway ) however I’m not a gambler. So I got an instillation last week or so- got buzzed and felt terrifically high off it like drunk and laughing that night and then bam – flat on my back with a terrible hangover for three days. So weird. Now reading this info you’ve posted – I am wondering what I am getting! I’ve never felt it so “poisonous” in my body before. Do the side effects change with different strains?

    I got Covid now so healthcare need 10 days isolation so I miss the next two doses. I don’t feel up to taking it right away and hope doc says I have to wait a certain amount of days after Covid before getting bcg. Anyone know? I’m just too tired to call doc at this point.

    Also interesting to note I am quite “well”with Covid other than low fever ; some cough ; sniffles and Lots of sneezing and generally no energy- so I read there’s study in bcg reducing Covid effects but then I’ve also had 4 vaccines.
    Sorry a bit off topic you posted here.
    <p style=”text-align: left;”>I do love to get  information but a lot of it is just too “heady” for me at this time – I’ve reread it three times now for full understanding:
    May I ask you some question?

    1) What is BC using for its bcg now? Would I be told if it changed up? Is there a shortage ?
    Do you know of any studies if the protocol isn’t followed precisely?

    Thanks Joe for the information you have shared here.
    Cheers- Tana</p>

    #43372
    Joe
    Participant

    Hi Tana, I am sorry to hear your have been experiencing the side effects of BCG.   I think Dr. Zlotta mentioned also in the pod cast about  a large study done awhile ago in the US.  The study said only 30% could finish the whole 3 years maintenance treatments.  So, you are not alone thinking of stopping the BCG before the completion of the 3 years maintenance course.  I think  you have done very good job so far.

    Incidentally, I have been guarantied in my bed room for the past 5 days because I developed sore throat, headache, coughing. But quick antigen tests  were all negative. Probably I got something from my grandson when he sneezed right on my face. I am still coughing.

    Your logic is correct to think about stopping because of toxicity,  especially when you seemed to have received  at least with two years span of maintenance treatment already.   I understand that your bladder developed semi chronic cystitis (bladder inflammation).    I will explain this from various angles and various testimonies by so called gurus on BCG treatment.

    1.   Your BCG treatment have not been given  with proactive preventive measure for side effects.   Dr. Ashish Kamat of MD Andersons cancer center in Texas says that the hospital treats  average 20 patients who receive BCG in a week.   In his practice, every patient is given quinolone 6 hours after BCG.     Quinolone is antibiotics, so some urologists think it is contraindication to BCG treatment as it may kill BCG bacteria.  But, he says okay because enough cytokines, which stimulate the immune system, would have been produced in 6 hours after the instillation of BCG.  He said Statins/aspirin therapy is okay, Antispasmodics are giving for local symptoms, Since the hospital started giving quinolone, the hospital hardly receives a phone call for BCG side effects.  Dr. Alan So of UBC is also saying in his educational presentation to UBC urology department that the usage of quinolone seems to be many urologists.   There was a small clinical trial  done in France.  Ofloxacin (TM) Flouroquinolone was given at 6 hours and then at 12 hours after instillation.  Side effects were reduced with no affect on efficacy. on  efficacy

    2. How much stopping of BCG now affects the progression free survival for the tumor original diagnosed as High Grade?    Dr. Kamat says the progression free survival rate (PDS)  of 1 year BCG and 3 years BCG are similar though with 3 years maintenance gives better (PSF).  Since you had already received 2 years of BCG, so you PFS  is better than  PDF of 1 year BCG but less better than PFS of 3 years.  The benefit is not much,  a study shows 5 year PSF for 3 years is 64.4% compared to 58.8% by 1 year.  It is 5.6% difference.  Since you had done 2 years already, 2.8% difference from 3 years technically speaking, but the study did not address that.  Also, another guru Dr. Michael O’Donnell of University of Iowa does not offer 3 years maintenance but stops after 2 years because in his practice, he saw little benefit adding the 3 year maintenance compared to increased toxicity.   The figure for the study is posted next, and the strategy treatment strategy employed by MD Andersons is also posted next.

    3. Reduction of dose to reduce toxicity :    Another well known guru is Dr. Lamm of University of Arizona – he is now have his private practice.  He is well respected by patients who participate in BCAN discussion forum because he used to answer questions from patients not necessarily his patients.   He was the chief investigator of the clinical trial (2000) which resulted in the recommendation of 3 years maintenance protocol.   He considers 3 years maintenance treatment gives the best efficacy.  I this the later study showed that too.  So, he will use 1/3 dose for maintenance treatment – note this is before the shortage. If he will use 1/10, 1/10oth if needed to reduce the side effects.   BCG cancer agency says it is okay to reduce to 1/3 dose because a study in Europe showed 1/3 dose did not affect efficacy much but 1/6 dose did.   So, this is dilemma.  If you are a patient of Dr. O’Donnell of University of Iowa. you will be likely be off BCG already.  If you are patient of Dr. Lamm, he will likely reduce the dosage to the level you do not suffer from toxicity but continue the 3 year maintenance.

    Hope this gives some background for your discussion with urologist.  I hope your urologist is the type who is willing to listen to the patient and explore different options, including from his or her clinical experience.

    best luck

    1 year vs 3 year  full dose vs 1-3 dose

     

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