Project Equity – Get Prepared 

Project Equity – Get Prepared 

Project Equity – Get Prepared | Blog Post – In 2013, the FDA published a report that reviewed clinical trials for seventy-two drugs, biologics, and Class III devices approved by the FDA in 2011. The report showed that while some sponsors were able to recruit subjects that accurately reflected the distribution of the disease in the population in terms of age and sex, the studies did not reflect participation by racial minorities and socially disadvantaged subgroups within the disease population. These results led the FDA to drive several initiatives to address diversity in clinical trials, the first of which was to issue a guidance in 2016 entitled Collection of Race and Ethnicity Data in Clinical Trials. 

In 2017, the US Congress enacted the FDA Reauthorization Act of 2017 (FDARA), which required the FDA to enhance diversity in clinical trials. As a result, the FDA published a guidance in 2020, Enhancing the Diversity of Clinical Trial Populations. 

Project Equity is an FDA Oncology Center of Excellence Initiative that aims to ensure that data submitted to the FDA for approval of oncology medical products adequately reflects the demographic representation of patients for whom the medical products are intended.  

The Food and Drug Omnibus Reform Act (FDORA) was signed into law in December 2022. This law includes provisions for clinical trial diversity and modernization. The requirement to submit Diversity Action Plans applies to Phase 3 and other pivotal clinical studies of drugs, biological products, and devices. One of the provisions of the Act was for the FDA to issue draft guidance on diversity action plans. 

In April 2022, the FDA issued a draft guidance encouraging sponsors to submit Diversity Action Plans that help ensure the adequate participation of relevant and underrepresented populations in clinical trials. This guidance expanded on the 2016 FDA guidance, and submission of the diversity plans in accordance with the draft guidance has been voluntary so far.  

Since the draft document was in effect, the FDA has reviewed plans and received comments from sponsor companies. Between April 13, 2022, and April 13, 2023, the Oncology Division received 76 Diversity Plans from 42 unique companies, and the Division provided feedback on 31. Additionally, the FDA has received 105 comments from the Industry on the draft guidance. FDA is working hard to ensure that the final guidance addresses comments and concerns and provides needed clarifications. 

While we wait on the final guidance, the Industry needs to prepare now for when the guidance becomes final. Once the final guidance is issued, the requirement to submit Diversity Action Plans will apply to clinical studies that commence after the date, which is 180 days after the publication of the final guidance. This may seem like a long time, but it will go by quickly.  

All sponsors and CROs must keep this new requirement at the top of their minds when designing and implementing new clinical trials. These plans take time to develop, requiring protocol design and operational considerations. While big pharma has been an early adopter of these concepts, small biotech needs to consider them in their development plans. 

Diversity for pivotal trials is a challenging concept within the oncology space because racial and socioeconomic distribution differences within the disease population can make recruiting at major academic centers of excellence difficult. Furthermore, as we see more and more drugs approved through seamless design trials and accelerated approval processes, the need for diversity planning will be pulled into successively earlier phases of research. 

But there are actions that the Industry can take—and that sponsors can document in Diversity Action Plans—to reach these parts of the disease population. The major advantage to committing to Diversity Action Plans is not just compliance with future FDA regulations but rather ensuring the intrinsic validity of the study, thereby ensuring more accurate marketing claims. Enrollment into many oncology trials within specific populations can seem hard enough, but with the right strategies, commitment to diversity does not need to hamper enrollment goals. 

OncoBay Clinical has helped biotech clients drive Diversity Action Plans and take actions to enhance diversity in their clinical trials to meet project equity requirements.

Craft Winning Strategies for Cash-Strapped Biotech Funding

Biotech funding: Raising money in a cash-strapped, depleted industry can be a daunting task.  If you want your best shot at raising the necessary cash for your program, you need to think strategically. A solid regulatory and clinical development strategy will be well worth the effort.  

First up is developing your target product profile. In completing this exercise, you can begin to assess your value and potential impact.  What can your assets accomplish?  Which indications have the most attractive market opportunities?  While those are relevant considerations, they are not the only considerations. 

The key to this exercise is to review competitor product reference labels from target regions of interest. This will aid in understanding what regulators have accepted, what they have not, and what may be a potential differentiator for your product. Also, part of this exercise is to understand the competitive environment for final marketing and the requisite clinical trials to get there.  It’s important to remember that you don’t want to evaluate the competitive space as it is now…where will it be by the time you get into the clinic or the market?  These considerations may ultimately lead to changing your target profile altogether.   

Biotech Funding

The power of this exercise is that it provides a solid goalpost and keeps the program on task. While there is never a guarantee for success, this type of careful assessment will help you be able to predict your decisions to keep moving forward or stop before too many resources have been burned.  

This type of information is also essential when raising funding. Investors don’t just want to see that you have positive results in animals; they want to understand how those results will translate to the patient and what impact the therapy can have on the market.  

At OncoBay Clinical, the leading global oncology CRO, we can empower your success in the competitive landscape. Our expertise enables you to craft a compelling investment narrative, ensuring your clinical development strategy aligns with regulatory expectations, market opportunities, and competitive dynamics. We provide comprehensive support, from developing your target product label profile to assessing the competitive environment, ensuring your program is on track for success. With OncoBay Clinical, you gain the insights and guidance needed to translate promising research into impactful therapies, attracting investors, and advancing your oncology program toward the market – partner with us to unlock your full potential and make a meaningful difference in the fight against cancer. 

Want to learn more about our services to support Biotech Funding? Contact us.
We are looking forward to hearing from you.

Cancer Diagnostics, Clinical Trials and the FDA

If you have any stake in an oncologic or hematologic asset, you are likely familiar with the topic of the significance of cancer diagnostics.  Even more so, if your asset is biomarker-driven, especially a non-traditional biomarker, then you are also likely familiar with the significance of the role of Companion Diagnostics (CDx).

It is a common understanding that oncologists treating advanced cancer patients must rapidly progress from insight to action. As such, they need comprehensive, reliable information regarding what exactly might be driving a patient’s cancer.  This is because we have an ever-expanding list of targeted options, also termed personalized medicine.  There have been massive advances in diagnostics and the development of drugs targeted to the diagnostic indicator. Improvements have come in leaps and bounds in regard to awareness, the adoption of comprehensive genomic profiling (CGP), and clinical accessibility.

This genetic profiling can guide informed decisions on available therapeutic options, most notably those that fall into the targeted therapy category, based on the unique genomic profile of a single patient’s tumor.

Currently, we know of hundreds of relevant genes known to drive cancer, including all guideline-recommended genes in solid tumors and additional genes that may be of relevance for targeted therapies in the future. This number is expected to continue to climb. Most importantly, these diagnostics can provide information on if and when a patient may benefit from a particular therapy.  In this scenario, there are FDA-approved companion diagnostics for FDA-approved therapies.  The FDA is now more deeply investing in the topic and its role in drug development.

In June, 2023, the FDA announced a new voluntary pilot program for certain oncology drug products used with certain corresponding in vitro diagnostic tests to help clinicians select appropriate cancer treatments for patients. More interestingly, in such, the FDA’s voluntary pilot program is intended to address the risks when targeted cancer treatments are approved without a companion diagnostic.

Companion diagnostic tests analyze human samples for biomarkers to help match patients to specific treatments. Typically, the FDA will approve a CDx and a therapeutic product contemporaneously, but in some circumstances, a cancer therapy that requires the use of a CDx will be approved even if a corresponding test has not yet received marketing authorization (1).

In these cases, healthcare providers may use tests developed by laboratories—a laboratory-developed test to make treatment decisions, which are intended to fill the gap merely but are not necessarily regulated by the FDA in the same way as other in vitro diagnostics (1).

The FDA views such laboratory developed tests as medical devices under its regulatory purview

This is raising concern with FDA  over the reliability and accuracy of such results which may be driving critical therapeutic decisions.  The FDA previously made a stand on the subject in 2015 when they published 20 case studies highlighting the potential dangers of unauthorized tests, including false negatives in detecting breast cancer and false positives in detecting ovarian cancer.

The FDA views such laboratory-developed tests as medical devices under its regulatory purview but exercises chooses not to enforce it at this time, so such testing developers are not required to submit a test for FDA approval. So how is quality and accuracy validated?  They are overseen by the Centers for Medicare and Medicaid Services through the Clinical Laboratory Improvement Amendments (CLIA). The CLIA requires labs to establish a test’s analytical validity when developed without FDA clearance or approva.

So here is the crux of the matter: even though CLIA requires analytical validity to be established, it does not require labs to establish clinical validity. So how accurately does a test identify people with a specific clinical condition or risk (1)? Such laboratory-developed diagnostics must seek FDA approval through the in vitro diagnostic pathway and are required to provide information about both analytical and clinical validity.

The newly announced FDA pilot program is designed to specifically address this regulatory gap and will publish minimum performance characteristics recommended for such diagnostics which are not authorized by the FDA. These will entail performance information for tests that were used to enroll clinical trial patients trials testing subsequently approved therapies and then post to its website the minimum recommended performance characteristics for similar tests that could be used after approval (1). Then, such diagnostic manufacturers can use the published characteristics to guide the development of such tests.

So, all onboard?  Not exactly. Many have expressed skepticism that the pilot program will be beneficial for the industry, noting that such lab derived diagnostics are still effectively unregulated regardless of whether companies participate. It is doubted that the FDA will not review any of the tests and thus are effectively legitimizing tests that FDA has never looked at, just taking word value from the manufacturer.

This leaves the manufacturer and corresponding drug developers to rely on their own evaluations of test performance and rely on gathered clinical trial data only.

OncoBay Clinical specializes in early-phase, biomarker-driven immunotherapy cancer trials.  We are well-versed in companion diagnostics and co-development CDx strategies.  Connect with us to hear more.

 

 

Sources:

  1. Shasteen, H: FDA Pilot Program for Cancer Diagnostics Met with Skepticism, 21Aug23

Continued Progress in the Relapse Refractory Multiple Myeloma Landscape

What a promising time for patients with heavily treated relapsed or multiple myeloma. The US FDA has granted 2 recent approvals which aim to further impact the lives of patients with this devastating disease.  However, if you are trying to bring a therapeutic asset through clinical development in this space, you may have to get behind two more available treatment options.

Until recently, relapsed or refractory multiple myeloma patients’ therapeutic options have been CAR-T, a second-generation proteasome inhibitor such as Carfilzomib (CAR) or Ixazomib (IXA), class-switching to a different class of drug with a novel mechanism, or the introduction of monoclonal antibody therapy.

Last spring (2022) Johnson & Johnson and Legend Biotech launched Carvykti, the 2nd approved CAR-T therapy for relapsed or refractory multiple myeloma post 4L+ standard of care, which continues to grow in multiple myeloma despite the introduction of what may be considered more convenient options, as it angles for earlier lines of treatment. The FDA has set April 5, 2024, as the target decision date for Carvykti’s application as a second- to fourth-line myeloma treatment.

Adding to the arsenal, on October 25, 2022, the US FDA granted accelerated approval to teclistamab-cqyv (Tecvayli, Janssen Biotech, Inc.), as the first bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager, for adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, those also required by Carvykti CAR-T therapy.

However, recently two more therapeutic options were added to the growing list of therapeutic options for patients with relapsed refractory multiple myeloma.

US-FDA granted accellerated approval

On August 10th 2023, the US FDA granted accelerated approval of TALVEY™ (talquetamab-tgvs) a first-in-class bispecific GPRC5D-directed CD3 T-cell engager for adult patients with multiple myeloma who have also failed at least the same four prior lines of therapy as the others.

Just days later, on Monday, August 14th 2023, the FDA approved another off-the-shelf, BCMA-directed drug, Pfizer’s Elrexfio, or elranatamab-bcmm, for the same indication. All four recent approved therapies -eligible patients will have to have had the gold standard of care multiple myeloma regimens of; a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody.

Elrexfio will be in direct competition with Johnson & Johnson’s Tecvayli, as both drugs are bispecific antibodies which assist T cells in targeting BCMA-expressing cancer cells.   Both therapies’ efficacy data are quite similar, both are sub-Q injections, but Elrexfio may have a convenience angle—yet the pitch has yet to be fully established.

Elrexfio, Tecvayli and Talvey are off-the-shelf drugs called “bispecific” antibodies, binding to proteins on both diseased cells and T cells to trigger an immune response.  While Elrexfio and Tecvayli both target a protein called BCMA that’s found on malignant plasma cells, Talvey is aimed at another one known as GPRC5D. All of these newer multiple myeloma drugs have immune-related side effects that can require hospitalization or stays nearby for monitoring.

These new multiple myeloma drugs are immune-therapies, and therefore have immune-related side effects that can require hospitalization or ‘close vicinity’ stays  for monitoring.  For Elrexfio, the FDA is mandating a 48-hour hospital stay after the first dose and 24 hours after the second dose in a “step-up” schedule. Patients taking Tecvayli and Talvey must stay 48 hours in the hospital after each of their step-up doses.  Elrexfio has a single fixed dose, while Tecvayli and Talvey’s dose is weight-dependent. Once the step-up period is completed, patients receive an Elrexfio shot every other week, compared with the weekly shots of the J&J drugs.

Burgundy Red Ribbon

Adobe Stock | 482524977

Talvey – a bispecific antibody

Talvey is a bispecific antibody targeting T-cell CD-3 receptors and G protein-coupled receptor class C group 5 member D (GPRC5D) developed by Janssen. The regulatory decision was based on the talquetamab Phase 2 MonumenTAL-1 study, which included patients who had received at least four prior lines of therapy and who were not exposed to prior T-cell redirection therapy.  This trial showed meaningful overall response rates (ORR).of 73.6% (95 percent Confidence Interval [CI], range, 63.0 to 82.4) with a median follow-up of nearly 6 (range, 0 to 9.5) months from first response among responders, 58 percent of patients achieved a very good partial response (VGPR) or better, including 33% of patients achieving a complete response (CR) or better. Responses were durable with a median duration of response not reached in the 0.8 mg/kg SC biweekly dose group and 9.5 months in the 0.4 mg/kg SC weekly dose group.  Among patients receiving the 0.8 mg/kg SC biweekly dose, an estimated 85 percent of responders maintained response for at least 9 months

The regulatory decision for Elrexfio is supported by data from the phase 2 MagnetisMM-3 trial (NCT04649359), which showed that elranatamab elicited an overall response rate (ORR) of 57.7% (95% CI, 47.3%-67.7%) in roughly 100, BCMA-directed therapy naive patients.  The data boasted a complete response (CR) rate of 25.8%, a very good partial response (VGPR) rate of 25.8, and a partial response (PR) rate of 6.2%. Notably, 82% of responders were estimated to continue to respond to treatment for 9 months or longer. The median time to response was 1.22 months (range, 0.9-6.5), and the median duration of response (DOR) was not yet reached (NR; 95% CI, 12.0-not evaluable [NE]). At a median follow-up of 11.1 months (95% CI, 10.6-12.0), the 6-month and 9-month DOR rates were 90.4% (95% CI, 78.4%-95.9%) and 82.3% (95% CI, 67.1%-90.9%), respectively (see FDA release for details).

What’s to come?

Of special note, Pfizer advanced this first-in-patient trial to approval in less than five years, which is impressive to say the least.  Yet, continued approval is contingent upon further verification and validation of clinical benefit in the confirmatory, PIII MagnetisMM-5 trial (NCT05020236). in patients with double class–exposed, relapsed/refractory disease.

Overall message, great news for patients needing treatment options for multiple myeloma, bad news for those with potential assets in clinical development, as this continues to be a highly competitive space as both investigator sites and patients have many options to turn to over clinical trial participation.

OncoBay Clinical specializes in immune-oncology with deep experience in relapsed refractory multiple myeloma. Our deep academic acumen can be instrumental in maneuvering through this competitive space and bringing your study to the forefront of focus.

Talent in the CRO Settings

We all well know from personal experience or just general knowledge of the field that large CROs have a plethora of varietal resource.  They also may have a ‘front man crew’ of significant talent. Yet, it is generally a gamble for our clients whether they actually will get such talent or resources allocated to their trial.  Here is yet another example of what sets us apart at OncoBay.  We limit our resources to the utmost talent and only put forth resources we believe add more value than cost.  So why the difference? Profit over Process over Patient.

Larger CROs have a greater financial burden to power such a mothership afloat. They have a tremendous  responsibility to their investment community.  CROs notably get a bad rap – like a sleezy used car salesman.  One of the topics concerning pharma/biotechs is whether financial benefit for managing studies with extended timelines may drive those that seem to take much longer than possibly they should.  Have we actually slipped into a “process over patient” field?    Some say yes, the large box CROs may have.  It is something we, OncoBay, can proudly state otherwise, but must remain watchful to ensure we actively never do.  Patient centricity, followed by data integrity, must remain our top priority.

Outside of clear direct quality concerns of; potential patient impact, cost to client and possibly even impact to data integrity, there is also an indirect impact to such, leakage of quality talent.  Those of us that do not want to play a role in a system that does not align with our personal integrity.

Titel Image „Talent in CROs“

There are many key reasons why top talent is hard to keep and why we must strive to ensure we do not fall into these habits as an organization:

  1. Misappropriated scope of talent – going after the available over strategically going after key people with key attributes to fill important gaps
  2. Poor talent acquisition methods – lengthy and time-consuming, deliverable-based process, as well as poor and/or inaccurate communications
  3. Too much focus on what’s on paper and less on who they are and how they approach work – lacking a consistent and meaningful interview methodology
  4. Poor management personnel – ~ 80% of people leave their job because of their boss.  The failure here is assuming that people who are good at their job, will also be good managing people.  This is most often not the case.  Proper and effective line management is critical to engagement, satisfaction, quality and output.
  5. Organizational over-confidence – ‘we are too well established, too large and too strong to fail, everyone should be honored to work here..’ mentality.
  6. System Rigidity – a large rigid organization, such as large box CROs is where creative thought leadership, flexibility and adaptability go to die.  Some of the best talent who drive progress are creative, innovative thinkers, who will quickly leave when realizing their hands are tied and they cannot impart meaningful value.  Value is tied to purpose, and who wants to spend most of their time and energy performing tasks without the feeling of bringing value.  We become ‘valueless’ and leave.
  7. Evaluation and Compensation Inequity – from throwing money at those we feel the need to poach, without equalizing that value to those who already are dedicated to the company, to formulaic limits on both evaluations and compensation (directly tied).  This creates a chain of non-merit based compensation which seemingly cannot be broken and the entire organization, including the client, ultimately pays. This also includes the topic of inequitable rewards.  Many large companies, including large CROs create policies that ultimately do not truly connect value to reward.  This assumed, almost enforced status of performance mediocrity (aka forcing the majority of the organization to land in the middle/average range to limit pay and advancement expectations).  This again makes the talent feel their efforts and talent to be lacking in value.  It does not make them want to work harder, quite the opposite.  You either get complacency, or for the ambitious group, leakage.

As we tout our evolution from being a smaller, niche CROs, known for better understanding, valuing, and appreciating what the best talent can provide, we must ensure we do not compromise the qualities which innately facilitate our quality as a whole. It may sound cliché, but good clinical trials cannot be run without good people.

OncoBay was founded to challenge the failures of large CRO’s rigidity and mediocrity.  We have the unique ability to not only attract top tier, innovative talent, which large CROs do not seem to either want or attract, but to also nurture, reward and retain it.   In such, our clients also gain; quality, stable teams, efficiencies and cost savings.

Revolutionizing Cancer Immune Cell Therapy: Innovative Approaches to Enhance Targeting, Efficacy and Safety

Immune Cell Therapy Blog – A contribution by Brandon Fletcher, PhD – Medical Affairs, OncoBay Clinical

Immune Cell Therapy Blog Cover Image

Simply put, therapeutic immune cell therapeutics are primarily designed with three main objectives: to enhance/improve (1) target specificity, (2) efficacy, and (3) safety.

The earliest application of leveraging living immune cells as a therapeutic began getting attention in the late 1980’s, when tumor-infiltrating T cells (TILs), isolated from human cancer tumors were used to treat metastatic melanoma NCI, Rosenberg).  Such endeavors fueled the immune cell therapy category ranging from cancer, to infectious disease to autoimmune disease.  Out of the 32 FDA approved cell and gene therapies, the evolution of adoptive cell transfer (ACT) therapeutics from the original TIL work has brought us 6 approved and clinical-medicine altering therapeutics for cancer patients in just the past 5 years, with TIL therapy on the heels of approval.

However, yet we are still working out the kinks, as the challenges were not inconsequential; 1) the isolation/preparation of large numbers of ‘functional’ immune cells (mostly T), native tumor-suppression (evolution within tumors to evade and/or suppress attack, immune cell exhaustion (immune cell loss of function in tumor microenvironment and/or areas of high tumor antigen burden.  So the industry pivoted slightly to broaden our arsenal.

In such, we began exploring the manipulation, basically the genetic engineering of immune cells, which can be performed either ex vivo prior to infusion of the cell therapy or directly in the subject. Genetic engineering has played a critical role in the development of clinically effective cancer immunotherapies, most notably in the broader categories of; engineering of antigen receptors (CARs and TCRs etc.), pathway manipulation (genetic modification of intracellular pathways that modulate natural processes related to tumor survival [proliferation, metabolism, destruction etc.]), and bringing forth genes that provide new functions to immune cells, aka accessory genes.

Currently, the main target cell in such ACTs has been the T cell, for obvious reasons.  However, the immune cell of choice continues to be challenged and we are developing potential therapeutics also using alpha/beta T cells, gamma delta T cells, natural killer (NK) cells, macrophages, marrow infiltrating lymphocytes and dendritic cells, to name just a few, derived in the autologous/patient-derived setting or the allogeneic/“off the shelf” settings.  Or even a step further, the cell may be ‘sourced/created’ through technologies using induced pluripotent stem cells (iPSCs) or entirely engineered cell lines.

Cancer immunotherapy (aka Immune-Oncology, I/O) has taken center-stage in the topic of promising medicinal advancements for cancer patients. There are thousands of I/O clinical trials and hundreds of companies developing all sorts of novel modalities and technologies, or addressing the challenges of the current modalities, however significant barriers remain, notably, those which may not be completely overcome by engineering strategies.  Antigen escape/antigen loss, duration of response due to cell exhaustion, heterogeneity of antigen expression, inefficient tumor infiltration, lack of persistence, and natural or tumor-derived immunosuppression – all continue to be a challenge. Moreover, although we have made strides in the critical-toxicity profile of immune cell therapies, such as CRS and ICANs, they remain a significant concern.  How are we attempting to address these concerns?  Genetic manipulation.

Ongoing efforts in ex vivo and in vivo cell engineering are underway to address each of these challenges. A full depth and breadth of these approaches is beyond the scope of this blog, but a few key examples are below to spark discussion (1).

Antigen Receptor Engineering

The buzzwords ‘Chimeric Antigen Receptor’ are likely spinning in our heads daily, as CARs are the most-studied receptors in ACTs. This receptor is engineered to fine-tune signaling, introduce remote controls, and to implement logic computation circuits (1). CARs incorporate both TCR and costimulatory receptor signaling domains that control T-cell proliferation, effector function, and metabolic fitness. An advantage of CARs over TCRs is their ability to target any surface antigen independent of patients’ MHC haplotype, but with the consequence of also having a lower antigen sensitivity.

TCRs are well known for their ability to target intracellular antigens, unlike standard CARs.  To address such differences, new hybrid receptor designs have emerged, such as TruCs (T cell Receptor fusion Constructs), which link antibody domains to different components of the TCR complex, STARs (Synthetic TCR and Antigen Receptors) and HITs (HLA-Independent TCRs) -which are both synthetic receptors fusing antibody binding domains to the native TCR receptor constant regions, and lastly, the multi-antigen approach of OR-gate CARs-which address antigen escape (1).

Ex vivo cell engineering

Engineered immune cells capable of sensing and ‘intelligently’ responding to various stimuli with measured efficacy continue to be developed. Here, the clinical cell design objectives are typically achieved through three genetic and molecular engineering approaches, such as: (i) receptor engineering, (ii) host cell genome engineering, and (iii) therapeutic payload co-engineering – all three warranting significant further safety and efficacy exploration (1).

Therapeutic payload co-engineering

Engineering immune cells to express therapeutic payloads provides an additional opportunity for modulating cell function. When combined with CAR expression, they are sometimes referred to as “armored” CARs or TRUCKs (T-cells Redirected towards Universal Cytokine Killing).

Genome Engineering

Involves the engineering of the immune cell genome to enhance the safety and efficacy profile in cell therapy. Currently, such endeavors utilize engineered viruses, which randomly integrate payload DNA into the genome of donor cells, presenting the possibility of causing unregulated cell growth and cancer. Targeted integration at defined genomic locations, genome editing enzymes such as CRISPR/Cas is evolving to leverage electroporation with in efforts to remove the err that the genome editing enzyme will persist.

Immune cell manufacturing:

We are all well aware of the challenges in ACT manufacturing, which has certainly impacted their ease and potential. Logistics is the crux of these challenges, involving deep complexities in managing chain-of-custody and chain-of-identity of all the ‘living’ materials. Furthermore is the concern over utilizing viral transduction to deliver DNA payloads, which has a high failure rate. Hence, we are seeing an expansion of non-viral approaches to gene delivery, and  significant resources have been devoted to developing allogeneic/“off-the-shelf” cell therapeutics.

In vivo cell engineering

These technologies include materials used to place transferred immune cells at the desired site, targeting of transferred cells via externally controlled cues, and direct genetic manipulation in the organism/human.

This is such an exciting time for cancer discovery and promise for patients.  We at OncoBay are focused on immune-oncology therapies, with the lead focus on cell therapeutics. 85% of our staff are deeply experienced in cell therapy, and we average over 15 years’ experience in the field, yet, even we continue to be in awe of the accelerated pace to meaningful outcomes in the cell therapy space.  The opportunities, angles, strategies and novel modalities appear to be endless.  Is there room for predictive computational modeling and AI-based data analysis here? What about the correlative application of larger systems  to better describe the interactions of cell therapies with the endogenous immune system, the nervous system?  Lastly, what might be the role of the gut microbiome in neo-oncogenesis and tumor proliferation and survival?  We would love to hear your thoughts.

 

References:

  1. Irvine DJ, Maus MV, Mooney DJ, Wong WW. The future of engineered immune cell therapies. Science. 2022 Nov 25;378(6622):853-858. doi: 10.1126/science.abq6990. Epub 2022 Nov 24. PMID: 36423279; PMCID: PMC9919886.

Phase I Oncology Trials: An Evolving Paradigm

Phase I studies are the cornerstone of translating findings from preclinical research into clinical practice and are used to determine the recommended dose and schedule of an experimental therapeutic (1). For decades, phase I oncology trials have been termed ‘toxicity trials’ or ‘safety trials’ and were considered to have low clinical utility other than that of establishing the toxicity profile of emerging therapeutics. Why? This is because phase I trials were thought to be solely aimed at elucidating the toxicity and pharmacokinetic profiles of investigational therapeutics with limited or no therapeutic intent.  Efficacy was not addressed.

The traditional distinction of the three-phase trial algorithm has been challenged in the past few years, most notably in the oncology space by the introduction of targeted therapies and immunotherapies into the cancer care model.  This transformation has especially affected early phase trials, leading to the current situation in which response rates are increasingly addressed and reported from phase I trials. A recent analysis shows that, despite their focus on safety, phase 1 trials of new cancer treatments may benefit participants more than previously thought.  This analysis revealed that over the past 2 decades, the number of phase I solid tumor trial participants whose tumors shrank or disappeared nearly doubled and the percentage of patients whose tumors stopped growing for a time also increased. The risk of death caused by a new treatment being tested, however, remained steady and very low, at less than 1% (2).

We all bear witness to the progressive evolution of perceptions, acceptance, and in many of opinion, the value of phase I trials, especially in the oncology setting.  Still yet, the perception of the potential benefit to patients has not caught up with current drug development. Historically, patients in phase 1 trials generally have had suboptimal tumor response rates, at roughly 4%–5%. Moreover, the primary purpose of phase 1 trials remains all about the assessment of safety with elements of supportive ADME data. So, some doctors have lacking in support in referring patients to phase 1 trials.

But we and others have now shown that things have changed. Participating in phase 1 trials has more potential for clinical benefit than is commonly believed, largely due to the development of modern cancer drugs, like targeted therapies, immunotherapies, regenerative medicines, such as cell and gene therapeutics as well as new combination therapies.

Oncology Clinical Trials Title Image

This is not to say safety does not still rule the roost in phase I trials. The determination of the toxicity/safety profile of a novel therapeutic will always be the crux of phase I clinical trials; yet, as ‘Precision Medicine’ continues to evolve and bring increasing access to biomarker-based, molecularly targeted therapeutics which further refine patient selection, more and more phase I trials can have a therapeutic aim. Not to forget, there is a move to incorporate phase II extensions to demonstrate efficacy in the phase I setting.  We also better understand our therapeutics at an earlier stage in drug development, especially in oncology which has been driven by having sequenced the entire genome and the readily available next generation sequencing.  In such, oncologic drug development, investigation products have well-defined mechanisms of action (MOA) and targets having potential of rapid determination of efficacy through creative phase I trials designed to enrolling much larger volumes of patients than we have seen in the past.

You can see this trend yourself, just look at FDA approvals in the past few years where several investigational products have been approved on the basis of results from phase I studies.   Yes, approved, on the basis of PHASE I TRIALS (pembrolizumab/melanoma, ceritinib/NSCLC et al).  This is such a massive evolution to bringing novel and potentially beneficial therapies to patients sooner.  We applaud the FDA for so boldly prioritizing the critical and timely needs of cancer patients, but are keenly aware, we are still lacking a overall consensus on whether or not a favorable ORR translates into a survival advantage, as even promising phase II ORRs are not always predictive of survival benefits in subsequent phase III trials.

It is important to mention, OncoBay recognizes that phase I oncology trials encompass a variety of study designs and therapeutics with unique MOAs.  Add the potential benefit of adding surrogate end points, especially threshold values, to the trial design.

Efficacy outcomes may differ depending on the ‘n’ of the trial (did it include a large expansion cohort) and if the therapies tested involve combinations including approved agents versus non-approved agents as monotherapy. But, it is hard to argue the promise with Overall Response Rates are reaching around 40% (up from <5%) in current targeted phase I investigational therapeutics (those driven by a genomic biomarker being the highest).  Recall, the ORRs of approved oncology drugs as monotherapy are typically >20%, and FDA accelerated approval for oncologic agents generally sits around >30% (1).

Additionally, there are statistical considerations which have also evolved in the phase I setting. Randomized phase I study designs, and or those which incorporate dose-expansion cohorts are additional strategies to improve the statistical power and potentially enhance the readout of potential phase I therapeutic efficacy.

What are your thoughts around; the therapeutic intent of phase I trials, your perspective of if and how these trials have evolved, how this evolution has contributed to the concept that current phase I trials can be a therapeutic option for cancer patients, and what are the ethical considerations we should be addressing. We look forward to hearing from you.

Reference:

Unleashing the Potential of Technology: Tackling Challenges in Early Phase Oncology Clinical Trials

The fight against cancer is a battle that unites us all. As medical advancements continue to push the boundaries of science, early-phase oncology clinical trials emerge as a crucial frontier in pursuing effective treatments. These trials, conducted in the early stages of drug development, play a pivotal role in determining the efficacy and safety of potential therapies. However, they are not without their challenges. In this article, we will explore the unique hurdles faced in early-phase oncology clinical trials and outline strategies to address them, ultimately paving the way for groundbreaking discoveries and improved patient outcomes.

1. Patient Recruitment and Retention: The Foundation of Success

Patient recruitment and retention are essential yet challenging components of early-phase oncology clinical trials. With the development of targeted treatments, it has become increasingly difficult for researchers to identify eligible patients who meet the criteria for inclusion and exclusion in the trial. In addition, once participants are enrolled, there is an additional hurdle of keeping them engaged throughout the study. One must employ innovative strategies to address these challenges to maximize patient recruitment efforts and participant retention rates.

Besides reaching out to patient advocacy groups, partnering with local community physicians, and utilizing digital platforms to expand the pool of potential candidates, at OncoBay, we use our established site network, with more than 300 sites across North America and Europe. Utilizing technology to enable remote preselection of patients, to spare them unnecessary travels to the sites, is another solution to improve patient recruitment. With Genius ENGAGE and Genius ROSA, Oncobay has the right tools to obtain verbal and remote patient consent and conduct remote tele visits to perform prescreening activities. This approach has proven beneficial in including patients in a study, especially those in rare conditions.

Telemedicine can also significantly improve patient retention, allowing sponsors to replace traditional brick-and-mortar visits with a remote approach, sparing patients from unnecessary site visits and thus increasing patient comfort in participating in a trial. Furthermore, fostering strong relationships with participants and their families, educating them thoroughly about the trial’s purpose and protocol, and providing dedicated study coordinators on-site can help reduce drop-out rates and ensure optimal success throughout all trial phases.

Together, these efforts can help overcome any obstacles that may have previously hindered patient recruitment and retention success.

2. Regulatory Complexities: Navigating the Pathway to Approval

Navigating the complex regulatory landscape for early-phase oncology clinical trials is arduous. It requires a delicate balance between patient safety and expediting development, necessitating a profound understanding of relevant regulatory guidelines. Collaboration among researchers, regulatory authorities, and industry sponsors is essential to achieve this goal.

Establishing clear communication channels and actively seeking guidance from regulatory bodies can aid in streamlining the approval process and effectively managing potential delays. With significant experience in IND submissions and in preparing and hosting scientific advice meetings with regulatory authorities, OncoBay can support industry sponsors in finding the right regulatory strategy for their compound.

Leveraging innovative technologies such as electronic data capture systems and centralized monitoring can further facilitate compliance with applicable regulations while enhancing data quality control. To negotiate this demanding arena successfully, it is essential to take a proactive approach that encourages collaboration, proactively seeks guidance from regulatory bodies, and utilizes appropriate technologies. With thoughtful consideration and informed decision-making, it is possible to ensure that safety standards are upheld while optimizing efficacy to bring life-saving treatments to market faster.

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3. Data Management and Analysis: Maximizing Insights

Managing and analyzing complex data sets in early-phase oncology clinical trials is a substantial challenge. With advances in technology and the advent of precision medicine, the volume and complexity of data generated have grown exponentially. To address this challenge, researchers must embrace data management and analysis tools that enable efficient data collection, integration, and interpretation. Implementing robust data governance frameworks, utilizing artificial intelligence algorithms for data analysis, and fostering collaborations with data scientists can unlock valuable insights and facilitate evidence-based decision-making throughout the trial process.

OncoBay uses advanced analytics tools to enable drug developers to make informed decisions quickly and accurately based on real-time data. Through the capacity of sophisticated predictive models, advanced analytics allow researchers to understand their current situation better, identify areas of improvement in processes and operations, and take proactive steps to mitigate risks associated with upcoming initiatives. With access to timely insights from various sources, decision-makers can proactively assess the performance of their product and determine if further investments in the development of their product are beneficial. This is especially valuable during the early development phases of a product to save time and costs by terminating the development process of compounds that do not perform as expected. By taking advantage of advanced analytics, sponsors, and CROs can remain agile and stay ahead of challenges in clinical trials while making proactive decisions that will maximize their chances of success.

Conclusion

In conclusion, early-phase oncology clinical trials represent a critical juncture in the fight against cancer. By acknowledging and addressing the challenges of patient recruitment and retention, regulatory complexities, and data management, stakeholders can pave the way for groundbreaking discoveries and improved patient outcomes. Through collaboration, innovation, and a steadfast commitment to excellence, we can unleash the full potential of early-phase oncology clinical trials, bringing us one step closer to conquering cancer.

 

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