2nd FDA workshop for clinical trial design for NMIBC was held in November, 2021. Its contents have become available on internet.
This was a sequel to the 1st workshop held in 2013. The 2013 workshop was to address the need to develop new drugs for NMIBC as no new drugs had been approved for NMIBC since VALSTAR (valrubicin) was approved on 9/25/1998. The main outcome of the1st workshop was the definition of BCG Unresponsive. BCG Unresponsive means that there is a recurrence high risk NMIBC in spite of having completed "adequate" BCG treatment. A patient is considered having completed "adequate " BCG treatment is when the patient completed at least 5 weekly induction treatment and at least 2 weekly maintenance treatment. Since BCG Unresponsive was defined, several clinical trials have started for BCG Unresponsive NMIBC. The first drug which was approved by FDA for BCG Unresponsive is Pembrolizumab (Keytruda). The recent approval of Adstiladrin is the 2nd approval for BCG Unresponsive NMIBC.
The 2nd workshop was two day workshop. Day 1 was analysis of BCG shortage and its impact, and focused on BCG clinical trial design in a period of BCG shortage and Day 2 was on clinical trial on CIS and other subjects. The last session was how patients own experience can be implementing to the clinical trial design. I will focus on Dat 1,
Dr. Lerner if Baylor College, which is highly regarded in bladder cancer field has summarized the survey he conducted among urologist - academic center and community clinic how BCG shortage was handled and what changes they wanted to see.
Among all countries that were affected by BCG shortage, US and UK were only countries who decided not to bring in another BCG to mitigate risk to patients by BCG shortage. I will post later how each country tried to deal with BCG shortage later. Anyway, in 2019, AUA announced a joint statement of following strategies till the shortage has been resolved. Note that it was not an enforcement.
- BCG should not be used for low risk disease
- Intravesical chemotherapy first-line option for intermediate-risk NMIBC
- High-risk NMIBC prioritized for full-dose BCG. If not available, ½ to ⅓ dose.
- If supply exists for maintenance therapy, every attempt should be made to use ⅓ dose and limit dose to one year
- If BCG is not available, consider alternative chemotherapy options
- Consider radical cystectomy fo T1HG+CIS
The problem I see was that not all parties involved did not or could not follow the recommendations for various reasons as listed below.
- There was no code for hospital/urologist to charge 1/2 or 1/3 dose to insurance company.
- Academic hospitals were able to have patients to come in on the same day, so split doses could be administered, This was was not easy to local hospitals,
- Community urologists were very familiar to do BCG but not much on intravesical chemotherapy.
Below are the result of survey by 255 institutions - Academic 84, community, 150, hybrid 19, other 6
- Academic hospitals 84, Community hospitals 150, Hybrid 19, Other 6
- 61% of hospitals used shorter than 6 weeks induction treatment
- 68% of hospitals used less than full dose during the 6 weeks induction treatment
- 58% of hospitals gave no maintenance for up to 25% of their patients
- Majority of hospitals are not giving 3 years maintenance to high risk NMIBC due to the shortage
- 56% of hospitals preferred to treat with BCG for intermediate risk NMIBC in spite of the fact 219 Joint statement recommended intravesical chemotherapy. 33% of Academic hospitals used BCG but 66% of community hospitals used BCG for intermediate risk NMIBCs.
- 176 hospitals never had to borrow BCGs
- 100 hospitals (39%) said there would be adverse outcomes,i.e. progression to muscle invasive,due to the shortage.
- 92% of hospitals said the development of non-BCG based therapies as high priority for BCG-naive high risk NMIBC patients.
- 24% of hospitals said that the BCG shortage is affecting to enroll their patients in clinical trials in the BCG naive, refractor or unresponsive
The survey show very unfavorable results. I wonder if the result would have been much different if the guidelines for BCG shortage was an enforcement rather than recommendation.
Dr. Lerner said the urologists community was shocked to see those feedbacks. Urgent need to develop alternative to BCG has become a hot topic. This subject was discussed also in Day 1. Gemcitabine and Docetaxel sequential treatment is considered as a candidate. There is already a clinical trial BRIDGE started to compare Gemcitabine+Docetaxel against BCG for those patients who had never received BCG (BCG naïve). The investigator of the trial pointed out that also other issues need to be sorted out such it takes 30 minutes hospital stay for a BCG treatment and 3 hours for GEM/DOC. Right now, BCG treatment does not require preauthorization from insurance company but GEM/DOC does.
Re; exclusion of patients who had received reduce dose from the enrollment to clinical trials.
FDA said that they became aware of this issue since two years ago and hey have been working with drug manufacturers designing clinical trial how to include those patients with reduced dosage in clinical trial, for example by adding two cohorts - one for standard dosage, and another for 1/3 dosage. It still needs to work out this matter with parties with vested interest. The inclusion of those who received lower dose in clinical trial was concerned for urologists, so Dr. Lehner was happy to hear a progress on this matter at FDA.
copies of presentation in PDF and in video are available in the link
bit.ly/3TmorGy
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