"The Company (NOT regulators) stopped screening patients IMHO. That went unnoticed for a short time, and then the Company was forced to address why patient screening stopped." --RK
You just don't know that. The 10-K sure sounds like regulators placed the hold:
In addition, our Phase III trial of DCVax-L is on a partial clinical hold for new screening for enrollment. We do not know what will happen with this partial hold. We may not be released from the screening hold and may not be able to complete the planned enrollment in this trial.
The wording there is very interesting. There is only one kind of "partial clinical hold" in the world, and it's the one regulators impose on an IND. And "be released" is a passive stance. It implies a third party that has power over the situation other than the one speaking and would do the "releasing."
If the sponsor was halting screening of their own accord, the trials registry need not have changed at all. They've slowed to a crawl or stopped enrolling completely despite having dozens of sites open in the past. Remember in that 10-k where they had 20 sites or something and just "6 patients enrolled?" The sponsor controls that flow. They can tell the sites to hold off for a time and they will. And they have to do this if they run out of cash (like they did when they were stuck at 22 patients in 2008). I think they were all told to stop screening and that the trial was put on partial clinical hold, as is their responsibility to disclose to all of the IRBs. The German trials entry apparently is the most thoroughly updated out of them all and this reflected that. Partial holds are material and are supposed to be PRed when they occur from a publicly traded company. -- Pyrr
Here's the thing, I actually do think it was confirmed to be company imposed. The line you quoted to me means they need regulators to LIFT it. Here's the summer PR:
NW Bio Confirms Phase III Trial of DCVax®-L for GBM Brain Cancer Is Ongoing
Patients In Trial Continuing To Be Treated Per Protocol, Including In Germany
BETHESDA, MD, August 21, 2015 - Northwest Biotherapeutics (NASDAQ: NWBO) ("NW Bio"), a U.S. biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, confirmed today that its Phase III trial of DCVax®-L for newly diagnosed glioblastoma multiforme (GBM) is ongoing and the patients enrolled in the trial are continuing to be treated per the protocol.
Over 300 patients have been recruited for the trial. The total anticipated enrollment is 348 patients.
The only change in status of the trial is that new screening of patient candidates for the trial has been temporarily suspended while the Company submits certain information from the trial for regulatory review.
Such screening involves the initial evaluation of patient candidates to determine whether they meet eligibility criteria for the trial (e.g., whether they are within the eligible age range, do not have certain viral diseases, etc.)
Some blogs and social media comments have noted that the EudraCT trials database in Europe states that there is a "Temporary Halt" of the trial in Germany. In actuality, the trial status in Germany is that the trial is ongoing as noted above, and the Company has only undertaken a temporary suspension of new screening.
The Company has sought to have the EudraCT listing corrected, but the database includes only certain pre-specified categories and there is no category that corresponds to a temporary suspension of new screening only, while a trial is ongoing.
The Company is in the process of preparing the trial information for regulatory review and anticipates submission within the next couple of weeks.
Item 8.01 Other Events. On Friday, August 21, 2015, the Company issued a press release confirming that the Company’s Phase III clinical trial of DCVax®-L for newly diagnosed Glioblastoma multiforme is ongoing and all patients in the trial are continuing to be treated in accordance with the protocol. The Company reported that over 300 patients have been recruited for the trial. The Company reported that the only change in the status of the trial is that new screening of patient candidates has been suspended while the Company prepares and submits certain information from the trial for regulatory review. A copy of the press release is attached as Exhibit 99.1.
The Company received various shareholder inquiries, asking whether the 300 patients are actually enrolled and being treated in the trial, or were just screened for the trial. On Monday, August 24, the Company responded by confirming that the 300 patients are actually enrolled and being treated in the trial. The Company also noted that being in the trial means not being in the Information Arm, and not being in the pseudo-progression arm, each of which are parallel with the trial but outside the trial.
A shareholder inquiry also asked what information the Company is submitting to regulators. The Company’s response noted that such submissions would not normally be discussed in the middle of a regulatory process or dialog, and that the Company plans to report when the process has been completed.
A copy of the shareholder reply is attached as Exhibit 99.2.
Anyway, from that, I think it's impossible to say that the Company didn't impose it themselves. To me, it truly reads as though they imposed it and future statements read as though they need regulators approval to screen additional patients. The below SEC risk statement, could simply have to do with their "planned" enrollment number, if they are going to try to increase the trial to include a co-primary endpoint of OS. I don't think main arm pseudos are affecting the trial as much as AVII thinks. I think that the fact that they get a maximum resection, that main arm pseudos they see will be distance metastases, and not local metastases. BUT, I do see that even a few cases could negatively skew PFS, and so the Company will use those instances of imaging "immunotherapy" false progression, to further de-risk the trial, and seek a co-endpoint.
Quote: In addition, our Phase III trial of DCVax-L is on a partial clinical hold for new screening for enrollment. We do not know what will happen with this partial hold. We may not be released from the screening hold and may not be able to complete the planned enrollment in this trial.
Again, I don't think MANUFACTURING is the reason for the hold. I think they SELF-IMPOSED it to obtain approval to make some protocol change, OS. BUT, they will need regulators to approve that protocol change. I continue to believe they will want to add a co-endpoint of Overall Survival to further de-risk the trial. I don't know if they will be successful in that pursuit, as upon crossover, patients are not on standardized therapy. If that is not approved, the study will not be in jeopardy of stopping as regulators will allow a study to continue that has ALL patients living longer, without knowing if it's the vaccine or not contributing to that outcome. If they do not get a co-endpoint approval, I continue to believe they will seek to add more patients to the trial, as crossover has ALL patients living longer, they need to have more events to get to their secondary endpoint.
I also believe that while the trial has been on self-imposed screening hold they have been pursuing manufacturing hub updates. If it is as you said it is, and that they haven't tested TFF manufacturing, then perhaps they are submitting Direct manufacturing data to regulators. That said, I believe they incorporate that TFF change in 2014, as indicated by their August 2014 PR. I believe the new protocol allows for a new manufacturing method. However, if you are correct, and they did not, THEN I believe they will want to test that method in patients, before the study ends, so that HE patients can be on that methods.
You think the vaccine is nothing but a placebo and that all patients are living longer because they are healthier to start off. Meanwhile, I see that being the patients are healthier at the start of immunotherapy that they will be able to receive the vaccine for longer timeframe. And past studies have shown that patients who live longer end up having more of an immunotherapy response, specific to the vaccine. Point is to get the patients over that longevity hurdle, so that the vaccine has the time to improve the immune response. What happens when crossover patients with better immune systems qualify for a second surgery, and then get the vaccine (that has BCG and IFNy)? To me it means they will potentially live long enough for the immunotherapy to work. And therefore, they might not be enough OS events in both arms. If the study is in any jeopardy of falling short on their primary PFS endpoint (due to advances in SoC - surgery, will procure better PFS in their ITT population (placebo arm)) the Company will NOT want to unblind the Phase III data until it reaches it secondary endpoint (assuming a co-endpoint isn't approved). The study will therefore need to add patients as it will need to get to OS endpoint, and the only way to do that is to add more patients.
As for where they are in the current screening-hold lift process, I believe they have the co-primary endpoint decision in hand (yes or no) and/or trial size increase (yes), and THEY are waiting for MANUFACTURING site clearances to resume enrollment. They NEED regulators to LIFT the screening hold to allow them to screen more patients to new manufacturing. Once they get all site clearances, they will let us know recruiting will begin again.
Happy Sunday. :)
And interesting article from ASCO:
Immunotherapy Could Be the Wave of the Future, but Problems and Challenges Cannot Be Ignored
By Margot J. Fromer April 25, 2016
Immunotherapy is on its way. A few agents have already been approved: ipilimumab (Yervoy) in 2011 for melanoma; nivolumab (Opdivo) in 2015 for non–small cell lung cancer (NSCLC) and then later that year for renal cell carcinoma; and pembrolizumab (Keytruda) for NSCLC. In addition, many clinical trials are showing great promise for this approach.
“Harnessing a patient’s immune system to fight disease offers several advantages over traditional drugs.” — Samir N. Khleif, MD
Samir N. Khleif, MD, Director, Georgia Cancer Center and Chairman of the National Cancer Policy Forum’s workshop, “Policy Issues in the Clinical Development and Use of Immunotherapy for Cancer Treatment,” said in his introduction: “Harnessing a patient’s immune system to fight disease offers several advantages over traditional drugs. In a healthy individual, the immune system acts with a high level of specificity to eliminate intruding antigens. Adaptive immunity creates immunologic memory after an initial exposure to a foreign pathogen, which in turn confers long-term protection in the event of future encounters. These benefits—specificity, memory, and adaptability—can be achieved through immunotherapy. It also generally produces fewer side effects than chemotherapy.”
Immunotherapy: What It Is, What It Can Do
Immunotherapy includes vaccines; immune modulators, such as agonists (stimulatory cytokines and costimulatory molecules) and inhibitors (checkpoint inhibitors and inhibitory cytokines); small molecules; and T-cell therapy. All of these approaches can be used alone, in combination with one another, and in combination with chemotherapy and/or radiation.
Developing them to the point of clinical utility presents a number of issues and challenges, said Dr. Khleif. For example: What preclinical data are needed in order to move agents and combinations to clinical trials? What dosing schedules will best provoke a response? How should clinical trials be designed? How can different developers and manufacturers create and market combinations? What will be the economic effects of these very expensive agents?
Steven A. Rosenberg, MD, PhD, Chief, National Cancer Institute (NCI) Surgery Branch, waxed enthusiastic about immunotherapy in general and cell-transfer therapy in particular. “With cell transfer, you can administer large numbers of highly selected cells with high avidity for tumor antigens. These cells can be activated ex vivo to exhibit antitumor effector function. This means that you can potentially identify exact cell subpopulations and effector function required for cancer regression in vivo. Moreover, you can manipulate the host prior to cell transfer to provide an altered environment for transferred cells.”
The photographs and scans he showed to demonstrate this strategy were dramatic: Huge fulminating cancers resolved into nothing more than scar tissue and multiple tumors darkening scans that melted into blankness in a few weeks.
“Based on recognition of immunogenic cancer mutations, adoptive cell therapy can mediate complete, durable, and likely curative regression of metastatic melanoma, even cases that have been refractory to other treatments. If you can achieve a complete response, it’s very likely to be durable,” said Dr. Rosenberg.
Malcolm K. Brenner, MD, PhD, Professor, Center for Gene Therapy, Baylor College of Medicine, added that in adoptive cellular immunotherapy, “T-cell–mediated cancer therapy is like monoclonal antibodies—only better. Specific receptors provide high targeting ability; they recognize internal antigens and provide good biodistribution; they are self-amplifying with multiple effector mechanisms; and the specificity of response can evolve with the tumor.”
Challenges in Preclinical Models
Helen Hislop, MD, DSc, Interim Director, Center for Cell and Gene Therapy, Baylor College of Medicine, described some of the challenges in preclinical models: In vitro studies are not always predictive; murine models have different immune systems and different target antigens from humans; and some mice are immunodeficient, which means that although human tumors can be engrafted, they may lack all necessary immune components.
In addition, said Dr. Heslop, preclinical models looking at cross-reactivity of virus-specific T cells had been misleading, predicting that cross reactivity may occur whereas this product has actually had an excellent safety profile in multiple trials in many centers.
“A mouse with cancer is not the same as a human with cancer,” said
Bernard A. Fox, PhD, Chief, Laboratory of Molecular and Tumor Immunology, Earle Chiles Research Institute, and CEO of UbiVac. “There are significant differences in the time it takes for a tumor to grow, and the tumor burden is different, as is immune selection. Moreover, different mouse models can give very different results, especially with combination therapy.”
Pilot studies in humans also are difficult because the number of patients is so small.
Cancer Vaccines
Vaccines present their own sets of challenges, said Dr. Fox. “They provide opportunities to advance the field of immunotherapy and improve patient care, but there are many gaps in the evidence.”
“Cancer vaccines are distinct from most other vaccines,” added Jay A. Berzofsky, MD, PhD, Chief, Vaccine Branch, NCI Center for Cancer Research. “They can harness exquisite specificity of the immune system to selectively target cancer cells, but to do so, we need to identify the molecules that are unique to, or highly overexpressed in, the cancer cells to be targeted with a vaccine. They must be clearly distinguished from normal cells,” he said.
“Longstanding cancers may have tolerized immune cells that could recognize them, so we need to overcome this tolerance. Moreover, cancers exploit immunosuppressive mechanisms to suppress the immune response against them, so we need to overcome this suppression as well,” Dr. Berzofsky continued.
“Vaccines require an intact immune system; they cannot be tested in xenograft models in immunodeficient mice; they can be affected by prior lymphodepleting treatment; and there must be an HLA match between T-cell specificity and target tissue, so syngeneic mouse models must be used.”
Because vaccines take time to mediate their effect and may slow tumor growth without causing regression, tumors may appear to progress before they regress, and overall survival may be improved without affecting progression-free survival. Therefore, vaccines cannot be evaluated with the usual RECIST criteria to which oncologists are accustomed.
Regulation and Approval
Whitney S. Helms, PhD, Supervisory Pharmacologist, U.S. Food and Drug Administration Department of Hematology and Oncology Products, described the difference between the two major offices of product regulation. The Center for Drug Evaluation and Research is responsible for chemical drugs, monoclonal antibodies, fusion proteins, and cytokines. The Center for Biologic Evaluation and Research oversees genetically modified T cells, cancer vaccines, and oncolytic vectors.
“To initiate a clinical trial for an anticancer drug, you usually need 28-day toxicology studies in two species, although for biologics, a single pharmacologically relevant species is often acceptable,” she said.
The preclinical program must have identified the pharmacologic properties of the agent, estimated a safe initial dose for the first human exposure, and explicated the toxicologic profile.
“With cancer immunotherapeutics, the challenges are even greater because species relevance has been a problem. This is what we look for: pharmacology of the targeted pathway, assessment of the cytokine-release potential, studies using human cells that take into account multiple mechanisms of action, and receptor occupancy.”
Dr. Helms said that the agency cannot rely solely on traditional toxicology studies for safety predictions for these products. “Therefore, thorough examination of the mechanism of immune activity is critical for first-in-human trials as well as throughout development and in the postmarketing period.”
Angela Thomas, PhD, Clinical Trials Chair, Biological and Vaccines Expert Advisory Group, Commission on Human Medicine, UK National Health Service, explained how things work abroad. “European pharmaceutical law allows a single marketplace, and licensing procedures are centralized as well. One application, one evaluation, and one authorization cover all European Union member states. The European Commission grants the license.”
Biologicals now constitute 27% of pharmaceutical sales in Europe; they have experienced a 5.5% growth rate vs 1.9% growth for the total pharmaceutical market. Many patents will expire before 2020, which allows for development of biosimilars and the potential for decreased cost and increased availability. This has already happened with two popular biologics: rituximab (MabThera in Europe), the patent for which expired in 2013, and trastuzumab (Herceptin), which expired in 2014. Two biosimilars have been approved for the former and one for the latter.
Challenges in Trial Design
“Immunotherapy trials are different from other clinical testing,” said Richard Simon, DSc, Chief, NCI Biometric Research Program. “Preclinical trial models are inadequate; the mechanism of action is more complex; phase I 3+3 design is not applicable; most immunotherapy requires combination regimens; and there are many candidate immunomodulating agents.”
In designing trials, biomarkers are critical, said Lisa Butterfield, PhD, Professor of Medicine, Immunologic Monitoring and Cellular Products Laboratory, University of Pittsburgh. They will avoid toxicity and the treatment it necessitates, they will avoid ineffective therapies for specific patients, they will lead to understanding of mechanisms of action and how to build on them, and they will aid in rational design of combination therapies.
Alas, adequate biomarkers are in short supply, she said. “We need the right specimens saved under standardized conditions. Variably banked specimens give ‘noisy’ data, and many trials bank only nonviable tumor and blood samples,” she explained.
“Immune assays can be costly,” she continued, “and testing small numbers doesn’t provide robust, reproducible signals.” Therefore, before any trial, one must be concerned about:
Prediction: Who should be enrolled? Prognostication: Who can benefit from a given therapy? Mechanism: What worked well or not well in a given intervention? Did the vaccine induce antitumor immunity? Did the intervention kill the tumor? Was immune suppression reversed? Was the signaling pathway blocked?
The SITC “Immunotherapy Biomarkers Task Force” is trying to help address needs in the field, with four working groups making recommendations on different areas of biomarker focus.
Immunotherapy in Practice
Immunotherapy can work for cancer patients; in a few cases it already does, but response patterns are different from traditional therapy. For example, the time to an antitumor response can be longer. Often, a clinical response is apparent only after a period of “pseudoprogression,” when immune cell infiltration can manifest as new lesions or growth of existing ones. Discontinuation of treatment is not appropriate until real disease progression is confirmed. Moreover, durable stable disease (without apparent tumor regression) may represent antitumor activity.
“Patient education is key to early detection because most [immunotherapy-related] adverse events, such as fatigue, headache, abdominal pain, colitis, and itchiness, can’t be identified on physical exam.”— Ramy Ibrahim, MD
Managing adverse events for immunotherapeutic agents can differ as well, said Ramy Ibrahim, MD, Clinical Vice President, Immune-Oncology, AstraZeneca. “The safety profile is based on the mechanism of action, and although adverse events can occur in any organ, the most commonly affected organs are gastrointestinal (diarrhea), dermatologic (rash, itchiness), hepatic (usually clinically asymptomatic elevation in transaminases), and endocrinopathies. Most adverse events are low grade in severity and manageable, but if not properly managed, symptoms can worsen, possibly to the point of irreversibility and/or the necessity to discontinue treatment.”
Dr. Ibrahim said there is no standard approach to identifying immune related adverse events, but any inflammatory event should be taken seriously and the use of steroids should be considered. “Patient education is key to early detection because most adverse events, such as fatigue, headache, abdominal pain, colitis, and itchiness, can’t be identified on physical exam and the treating physician has to rely on the patient to make him/her aware of any new symptom or worsening of existing symptoms. Patients are sometimes reluctant to report low-grade events because they want to continue treatment, and they tend to self-medicate and tell their oncologist only when the symptoms get worse. And if they go to a specialist for treatment, the oncologist might not find out about it and won’t be able to inform how they are being managed.”
Paying for immunotherapy will pose significant challenges because the Centers for Medicare & Medicaid Services and private insurers are having a hard time keeping up with approved and recommended indications for various cancers. For instance, the National Comprehensive Cancer Network® (NCCN®) recommended nivolumab for second-line treatment of NSCLC in June 2015, but some private payers were reluctant to cover it. This kind of response means that not only do patients run the risk of not getting the drug (or not having it reimbursed, which is tantamount to the same thing), but providers have to spend time and energy researching policies of all the insurers they deal with.
Coverage in the private sector is still spotty. Medicare is similar because its various contractors across the country have different policies about what they will cover.
The cost of these agents is staggering—higher than any previous class of cancer treatment. Therefore, payers are seeking better evidence that patients will clearly benefit, which brings the issue back to identifying biomarkers and their potential for predicting success.
Large-scale development and manufacture also poses problems. The first, said Eric Perakslis, PhD, Senior Vice President, Informatics, Takeda Pharmaceuticals, is interoperability—the ability of different information technology systems and software applications to communicate, exchange data, and use the information that has been exchanged. “Data exchange should permit information to be shared across clinicians, laboratories, hospitals, pharmacies, and patients regardless of the application or vendor.”
Dr. Brenner talked about the many problems that pharmaceutical companies and other entities face when deciding whether to collaborate or compete: “Publish or perish vs perish if publish,” puts the situation in a nutshell.
Mary M. Horowitz, MD, MS, Chief, Division of Hematology and Oncology, Medical College of Wisconsin, agreed and listed issues in establishing a mechanism for data integration and sharing for novel therapies. “It must capture all patients of interest as well as all data of interest, no matter where it is generated. It has to ensure data quality and maintain long-term follow-up. There must be confidentiality, security, and regulatory compliance, and the data must be available to multiple users.” ¦
