Mirror’s immunotherapy is unique in that it is not a pill or a protein, but instead is a living immune cell made into a drug called AlloStim^®.  AlloStim^® is derived from the blood of healthy donors.  Mirror has pioneered the methods for blood collection, blood cell component isolation, expansion and differentiation protocols and the harvesting, packaging, vialing,  freezing, shipping and distribution of the living cell drug product.  The Jerusalem manufacturing facility is capable to scale-up to commercial quantities of this living immune cell drug and methods for distribution are established currently in USA and SE Asia.

AlloStim^® is a novel living cell drug which has a novel mechanism of action.  Interestingly, AlloStim^® is designed to be rejected by the host immune system and does not directly engage to eliminate tumors or viral infected cells. Rather, AlloStim^® immune rejection acts in a manner that serves to re-program, rather than boost, the immune system.  Since AlloStim^® is quickly rejected by the host immune system, it does not persist long enough to cause any significant side-effects. The rejection of AlloStim^® releases ‘danger signals’ which serve as an adjuvant to reverse immune suppression and results in immunity to AlloStim^® which serves to modulate the host immune system to an enhanced state of cellular immune function. 

The immune system is capable of immune surveillance, constantly hunting down and then eliminating nascent tumor cells and viral infected cells before the aberrant cells form tumors or viruses spread to become disease.  Mirror believes cancer and viral disease to be a failure of this immune system surveillance function, which is mostly mediated by the innate and adaptive cellular immune system. Mirror’s unique approach targets re-programming of both the innate and adaptive immune cell components of a patient’s immune system in order to modulate a failed immune response into an effective response.

Many current immunotherapy approaches under development for cancer work to boost the resident failed immune response that originally allowed the disease to occur. The idea to boost the immune system of cancer patients assumes cancer is a disease of a weakened immune system. However, these immune boosting approaches often fail and sometimes make the disease worse. Mirror believes that cancer is a disease of a wrong immune response rather than a weak response. Boosting a failed immune system only provides a stronger failed immune response. Mirror’s approach is different, rather than boost a failed immune response, Mirror first modulates the immune system to change the immune response from a failed response to an effective response.  Once the immune system has been properly modulated to respond correctly to a tumor or virus, this new immune response can then be boosted. 

Metastatic cancer is a significant therapeutic challenge.  Tumors can be shrunk and life can be extended with chemotherapy and radiation, but metastatic disease generally can not be cured.  Harnessing the power of the immune system to cure cancer has long been sought out as a treatment strategy that could replace mainstay chemo-radiation therapy. While chemotherapy and radiation can extend life, these treatments are very harsh and some patients refuse or cut short these treatments as they feel it is not worth living longer without quality of life.  

For decades, the attempts to harness the immune system to control cancer have had disappointing results in the clinic, leading most oncologists at the time to believe that immunotherapy could never be more powerful than chemotherapy. However, the recent clinical success of checkpoint inhibition drugs has created more widespread awareness and acceptance of immunotherapy as a viable cancer treatment modality. These drugs have produced clinical responses and durable remissions in patients with a variety of cancers, including some with chemotherapy-refractory metastatic disease. 

These unprecedented results led Science magazine to select cancer immunotherapy as the 2013 “Breakthrough of the Year”.  The American Society of Clinical Oncology (ASCO) named Immunotherapy as the “Advance of the Year” in 2017 due to the continued success of the checkpoint inhibition drugs and the emerging potential of CAR-T adoptive immunotherapy approaches. 

In 2017, the FDA approved the first CAR-T drugs, opening a new category of immunotherapy using autologous living, genetically-engineered, cytolytic T-lymphocyte (CTL) “killer” T-cells as a drug.  Killer T-cells recognize tumors through interaction with a molecule called MHC I on the surface of cells.  However, tumors generally do not express MHC I, making them invisible to killer T cells. 

Tumor surface antigens are recognizable by antibodies. However, antibodies are ineffective at killing tumor cells.  To harness the killing power of killer T-cells and overcome the lack of MHC I expression on tumors, a strategy was developed to genetically modify killer T-cells so that they can recognize surface antigens like an antibody through a chimeric antigen receptor (CAR).  In this manner, a CAR-T is an engineered killer cell that can potentially recognize a tumor like an antibody, but kill like a killer T-cell. 

The genetic manipulation, expansion and adoptive transfer of autologous CAR-T is logistically complex and extremely expensive to translate to clinical use.  Genetic manipulation of the cells has resulted in some treated patients developing secondary tumors, causing US FDA to place a warning label on these products. Furthermore, this technology is only useful for directing an immune response against cell surface molecules. However, solid tumors do not express surface molecules that are unique to the cancer. For this reason, current CAR-T immunotherapy products are limited to blood cancer indications which can target a tissue type, like all B-cells.  

Mirror’s AlloStim^® immunotherapy has many advantages over CAR-T cells. While both are living immune cell therapies, AlloStim^® is not genetically-manipulated and is an allogeneic “off-the-shelf” product. As an “off-the-shelf” product, one blood donor can produce sufficient product for hundreds of patients, providing a significant economy of scale to lower cost.  CAR-T cells are manufactured for each individual patient. The lack of economy of scale makes CAR-T cells extremely expensive (~$500,000 per treatment).  In addition, CAR-T are highly toxic, requiring administration in a hospital in-patient setting, further increasing the cost. AlloStim has a very benign safety profile and is administered in an out-patient setting.

While AlloStim^® has significant advantages over checkpoint inhibitor and CAR-T immunotherapies, Mirror has a bigger vision than just to compete with these existing immunotherapies.  Mirror is seeking a future potential cure. Checkpoint inhibitor and CAR-T immunotherapies generally are not cures for cancer. To cure cancer, a treatment must eliminate every last microscopic cancer cell in the body and then provide continuous protection against disease recurrence.  Only by creating a cancer vaccine will there be potential for a cure.  However, therapeutic cancer vaccines have historically been the least effective immunotherapies under development.  Mirror intends to reverse this trend and create the first universally effect therapeutic cancer vaccine immunotherapy. A therapeutic vaccine treats existing disease, as opposed to standard vaccines designed to prevent disease.

The main cancer treatment modalities, including chemotherapy, radiation, surgery, and various new targeted therapies cannot completely eliminate tumors on a microscopic level, nor do they provide continuous protection from disease recurrence.  Only an immunotherapy that acts like a vaccine has the technological capability of producing a “cure”, as the vaccinated immune system can be trained to elicit both a “sterilizing” anti-tumor immune response followed by a “memory” response for long-term disease suppression.  Harnessing the curative potential of the human immune system through vaccination continues to be a major focus of cancer research efforts worldwide and is being pioneered by Mirror. 

Previous and current therapeutic cancer vaccine protocols have had difficulty in eliciting tumor-specific memory responses. A major obstacle faced in developing therapeutic cancer vaccines is the ability of tumors to evade and adapt to an effective anti-tumor immune response.  Tumors that evade immune destruction after therapeutic vaccination may have a selective advantage and become resistant to the elicited anti-tumor immune response through a mechanism known as tumor “immunoediting”. Immunoediting occurs when tumors escape initial immune elimination and accumulate further DNA mutations or changes in gene expression. These mutations exert selective pressure on the immune system, causing elimination of the more susceptible tumor clones and survival of the most resistant ones. Thus, incomplete immune elimination of tumors after vaccination often results in the development of new disease that is highly resistant to immune control 

The host immune system’s ability to protect against tumor growth and metastasis is known to be hindered by several factors, including:  (1) tumor immunoavoidance through tumor-induced impairment of antigen presentation, downregulation of MHC molecules, defective co-stimulation, and tumor production of immunosuppressive cytokines (such as IL-10 and TGF-β); (2) poor tumor antigen immunogenicity due to “self” nature; (3) heterogeneous expression of tumor antigens within tumors and in distant tumors; (4) tumor-influenced activation of tolerance-inducing immunosuppressive circuits, including  induction of suppressor regulatory T cells (Treg), suppressive natural killer T cells (NKT2), myeloid-derived suppressor cells (MDSC), and immunosuppressive subsets of mature dendritic cells (DC2); (5) loss of cellular immunity due to immunosenescence as we age and/or tumor-induced cellular immune suppression; and (6) immunosuppression due to heavy medical pretreatment and the presence of large tumor burdens. 

Cancer vaccine development continues to struggle with these obstacles while attempting to produce effective clinical responses. Mirror believes that anti-tumor mechanism that needs to be elicited by an effective therapeutic cancer vaccine must have both a spatial and a temporal component.  This is because immune deviation from permissive or suppressive anti-tumor responses can occur in different locations (lymph node, peripheral tissues, tumor stroma) and at different times. 

Multiple administrations of tumor antigens can result in high titers of circulating memory killer T-cells.  Standard vaccination practice, where tumor antigens are injected together with adjuvant, does not address the timing of the multiple decision points that occur during anti-tumor immune cascade development.  Also, standard vaccination protocols do not interfere with the bidirectional cross talk occurring between the existing tumor lesions and their surroundings, and consequently cannot stop the immunosuppression and avoidance mechanisms which facilitate tumor progression.  

The Mirror therapeutic vaccine protocols are the first to incorporate spatial and temporal components.  The Mirror therapeutic vaccine protocols feature weekly AlloStim^® injections over 3-4 months which alternate from intradermal (ID) to intravenous (IV).

The clinical benefit of past therapeutic cancer vaccines has been almost negligible despite the use of a variety of highly novel and innovative technologies, antigens, adjuvants and administration schedules. The obstacles impeding successful therapeutic cancer vaccine development are numerous and are extremely difficult to overcome.  The overwhelming complexity of these problems have caused many researchers to conclude that the development of an effective therapeutic cancer vaccine is not possible. 

Mirror, however, has been at the cutting edge of solving the problems of translating an effective therapeutic cancer vaccine to the clinic.  Mirror believes that the past failures of past and current extremely innovative therapeutic vaccine designs and new adjuvant technologies, it may be that these innovations represent solutions for the wrong problem.  Accordingly, a completely new approach was thought to be needed in order to design a clinically useful therapeutic cancer vaccine. Such a new approach must introduce a mechanism that is different from that has previously failed, as well as provide an explanation as to how the new approach would succeed in light of the numerous previously failed approaches.  

Rather than attempt to improve vaccine platforms that had previously failed, Mirror aimed to develop a next generation therapeutic immunotherapy vaccine platform patterned after an anti-tumor immune cascade that is already known to overcome tumor immune suppression and avoidance and to mediate tumor killing. The most powerful and only immune cascade known that is capable of eliminating chemotherapy-refractory metastatic disease is the graft vs. tumor (GVT) effect that occurs after allogeneic, non-myeloablative, stem cell transplant (ASCT) procedures.  Mirror has mapped this mechanism and reversed engineered the GVT effect into a host vs tumor (HVT) effect, which is the ‘mirror’ of the GVT effect.

The powerful GVT immune effect is proven capable of killing chemotherapy-resistant metastatic tumor lesions, but is intimately linked to a toxic side-effect known as graft vs. host disease (GVHD).  The high morbidity and mortality of GVHD severely limits the use of ASCT procedures.  The intimate and proportional relationship between the beneficial GVT effect and detrimental GVHD effect have made these effects difficult to separate.  The clinical application of the ASCT procedures is further complicated by the requirements for matched tissue donors, toxic chemotherapy conditioning and need to establish a stable chimeric immune system in order to observe GVT/GVHD effects. 

Mirror developed the “Mirror Effect” hypothesis to address the difficulties of harnessing the power of the GVT effect without GVHD toxicity.  The Mirror Effect hypothesis proposed to maintain the intimate relationship of the GVT/GVHD cascades, but reverse the direction of the immunological flow. In the reverse flow ‘Mirror Effect’ model, the effector cells are from the host, rather than from the graft, whereby there is a non-toxic host vs. graft (HVG) rejection, the ‘mirror’ of GVHD, as an adjuvant supporting a host vs. tumor (HVT) effect, the ‘mirror’ of GVT.  

To elicit the Mirror Effect mechanism in immunocompetent patients without requirement for first creating a chimeric immune system, Mirror designed AlloStim^®, to provide the same immune signaling as is provided by chemotherapy conditioning used prior to chimera formation and the same danger signals released by GVHD in ASCT procedures upon rejection by the host immune system. AllloStim^® is the first cell therapy designed to be rejected, rather than perform an effector function.

The alloantigens on the mismatched AlloStim^® cells serve as a potent immune stimulus. The immune mechanisms that influence responsiveness to the triggering allo-antigens hold the key to the ability to manipulate the immune system for therapeutic purposes.  The type of immune response that occurs after encounter with alloantigen depends upon the place the antigen recognition occurs and the inflammatory status of the microenvironment.  

Under non-inflammatory conditions, injections of alloantigens can cause the development of a tolerant response to the alloantigens. For this reason, the AlloStim^® cells must be administered with ant-CD3/anti-CD28-coated microbeads to assure they are activated and producing type 1 cytokines at the time of administration and rejection. This assures rejection results in enhanced cellular immunity to the alloantigens. When administered intradermally, the alloantigens from rejected AlloStim^® are processed by Langerhans cells (LCs), which are abundant in the skin, which then orchestrate the polarization of immune responses towards Th1 cellular immunity.  

The AlloStim^® protocols re-engineer the tumor microenvironment to create inflammation. In the context of this inflammation, which can be thought of as a vaccine adjuvant, the killing of tumor cells by activated NK cells recruited to the tumor releases tumor neoantigens.  The release of neoantigens and the adjuvant effect of the inflammation creates a personalized ‘in-situ’ vaccine.  This in-situ vaccine mechanism has the unique result of an off-the-shelf immunotherapy resulting in a patient-specific immune response customized to each patient’s own tumor.

Mirror is currently in late clinical development with novel immunotherapy, having  completed accrual in the StimVax clinical trial in metastatic colorectal cancer patients refractory to chemotherapy and immunotherapy. The  protocol uses 3 cycles of a combination of weekly intradermal AlloStim^® priming doses, which serves to increase the Th1/Th2 balance by increasing titers of allo-specific Th1/CTL and then at the end of each cycle an intravenous infusion which causes the extravasation of activated NK and memory T-cells to tumor lesions. 

In previous Phase IIA and Phase IIB studies in third-line microsatellite stable (MSS) metastatic colorectal cancer (known as ‘cold’ tumors unresponsive to immunotherapy), the subjects’ clinical presentation remained stable and median overall survival was approximately double the survival reported in historical controlled studies in this population.  Plans are now being made to advance AlloStim® to a registration trial in metastatic colorectal cancer.

Immune checkpoint blockade (ICB) immunotherapy has shown great potential and power in cancer treatment. However, these drugs only work in approximately 20% of human tumors that are characterized as highly inflamed ‘hot’ tumors.  The AlloStim® mechanism converts ‘cold’ tumors to ‘hot’ tumors, potentially broadening the market potential for ICB immunotherapy and providing potential for collaborations with the big pharma companies which dominate the ICB market.

Recently, Mirror Biologics announced clearance from US FDA and a collaboration with Merck, Darmstadt Germany for a new Phase II study of AlloStim in combination with Avelumab (Bavencio) in fourth-line metastatic colorectal cancer patients refractory to both chemotherapy and immunotherapy.

In another application of AlloStim®, Mirror Biologics has designed a vaccination method that modulates the immune system of elderly patients in a manner that converts the immune system from being senescent to one that works like a young healthy person. This conversion can  provide universal viral protection against both known and unknown viruses and their variants without the need to have prior knowledge of the antigenic and genetic phenotype of the viruses. In addition, this novel mechanism features a self-amplification mechanism which eliminates the need for annual booster injections. Mirror has completed a Phase I/II clinical trial in 40 healthy adults over 65yo with final results expected to be released early in 2025.

Mirror is thinking outside the box and is pioneering new ideas in immunotherapy of cancer and infectious disease. Mirror is on track to bring this new technology to the market and potentially benefit patients and society for the evils of cancer and the adverse effects of aging. 

The post MIRROR BIOLOGICS CREATING A NEW CLASS OF IMMUNOTHERAPY appeared first on ADRES biopharma regulatory consulting.

The Evolving Expectations in Clinical Trials

Recent updates to the ICH GCP guidelines, particularly Revision 3, have placed sharper focus on sponsor oversight. The revisions make explicit what was once implied: sponsors must proactively ensure that all aspects of a clinical trial—from design to data integrity—meet high standards of quality and regulatory compliance. This includes:

• Performing early risk assessments
• Conducting thorough vendor qualification and requalification
• Auditing clinical sites and operations
• Validating computerized systems

These activities are no longer optional best practices; they are regulatory expectations. Section 3.9.1 of ICH E6(R3) specifies that the sponsor must ensure that the trial design and conduct result in reliable data and the protection of trial participants. This translates to clear documentation, traceability, and robust systems that prevent, detect, and correct deviations.

What to Include in Vendor Contracts

Vendor agreements should function as both legal safeguards and operational playbooks. They must:

• Mandate adherence to trial protocols and regulatory standards
• Define data recording and retention responsibilities
• Allow audits and inspections by regulatory bodies
• Address cross-border data handling, language considerations, and time zone coordination

Sponsors must also establish clear lines of responsibility, especially in multi-vendor environments. Agreements should outline escalation procedures in case of deviations and ensure vendors agree to inspections by authorities such as the FDA or EMA.

Data Privacy is Everyone’s Business

GDPR adds another layer of complexity. Under this regulation, sponsors are data controllers—ultimately accountable for how personal data is processed throughout the trial lifecycle. Compliance requires:

• Rigorous due diligence on vendor security practices
• Data Processing Agreements (DPAs) to govern roles, responsibilities, and breach response protocols
• Transfer Impact Assessments (TIAs) and Standard Contractual Clauses (SCCs) for vendors outside the EEA

Documentation is critical. Sponsors must maintain a Record of Processing Activities (ROPA) and conduct Data Protection Impact Assessments (DPIAs) for each trial that poses a high risk to participant rights. During vendor audits, ensure subprocessors are disclosed and approved, and that policies for data subject rights and breach response are in place.

Guidance for Compliance: Beyond the Basics

The webinar highlighted best practices sponsors should implement:

1. Integrated audits: Conduct GCP and GDPR audits in tandem to streamline oversight and avoid compliance gaps.
2. Early engagement of a DPO: Data Protection Officers should review all processing activities and vendor contracts from the start.
3. Policy-driven oversight: Sponsors should implement SOPs on breach notification, data subject rights, and subcontractor approval.
4. Training: GDPR literacy among trial staff is essential, even for non-legal roles. Staff must recognize compliance risks and know how to respond.

Lessons from the Field

Vendor missteps can have serious consequences. In one illustrative case, a sponsor nearly enlisted a trial site with an unresolved FDA warning letter. The oversight could have been caught earlier through a regulatory check. In another example, unclear data transfer agreements led to delayed startup times across multiple geographies.

To avoid such issues, sponsors should treat vendor selection as a strategic decision, not just an operational one. Build in checkpoints for performance evaluation, require transparent metrics from vendors, and have a defined escalation path for compliance concerns.

Small Sponsors, Big Stakes

For small biopharma firms, the regulatory burden may feel outsized. But scalable solutions exist:

• Appoint a quality assurance lead early in development
• Develop a core set of SOPs tailored to your trial’s complexity
• Leverage experienced consultants for both GCP and GDPR compliance
• Use predefined audit templates and questionnaires to assess vendors systematically
• Invest in training so internal teams can identify and mitigate risks early

Small organizations can be just as compliant as large ones if they are proactive and strategic.

Conclusion

Vendor selection in clinical research isn’t just a procurement task—it’s a cornerstone of trial integrity and regulatory compliance. By approaching vendor partnerships with diligence, transparency, and foresight, sponsors can safeguard not only their studies but also the rights and data of their trial participants.

Compliance, in the end, is not a box-ticking exercise. It’s a mindset. Sponsors who embrace this will be better equipped to navigate the increasingly complex terrain of global clinical research.

Looking for expert guidance?

Connect with ADRES for strategic GCP and quality assurance support tailored to startups and growing biopharma companies. www.adres.bio

Need help with GDPR compliance? Reach out to RD Privacy for hands-on support in data protection strategies and vendor oversight across clinical trials. www.rdprivacy.com

The post Navigating GCP and GDPR in Vendor Selection: Key Responsibilities for Sponsors appeared first on ADRES biopharma regulatory consulting.

Breaking Down U.S. Market Access 

For those new to the concept, U.S. market access can be understood through four key components: 

1. Reimbursement – Reimbursement covers payer medical policy coverage decisions, appropriate coding, and ensuring fair payment rates. It also encompasses billing processes and programs that support patient access to care. 

2. Clinical/Health Economics/Patient & Provider Impact – Demonstrating the value of a medical innovation requires robust data, including clinical effectiveness, cost-efficiency, and its potential impact on patient and provider experience. 

3. Stakeholder-Specific Value – Different stakeholders, including payers, providers, patients, and policymakers have unique priorities. A successful strategy addresses these specific needs to support adoption and use. 

4. Managed Care Payer Strategies – Medicare, Medicaid, Commercial Insurance, companies as well as self-insured employers and health systems play a central role in patient access. Establishing a cohesive payer access plan is critical to success.  

Together, these components emphasize the need for a coordinated and evidence-based approach to navigate complex healthcare payers like Medicare, Medicaid, and private insurance. 

An Example of Market Access in Action: Prostate Cancer Diagnostic Test 

A recent example of effective market access involved a prostate cancer AI molecular diagnostic test facing challenges with proposed Medicare reimbursement. The Centers for Medicare & Medicaid Services (CMS) initially proposed a reimbursement rate of $760 per test, which did not align with the test’s complexity, resource utilization and costs. 

Dream Big Health market access consulting played a key role in supporting the test’s pricing strategy. Despite an initial rejection of our crosswalk pricing recommendation, we worked closely with the client to develop a structured approach to rebut Medicare’s proposed pricing.  

• Drafting and submitting a letter to CMS detailing critical technological, process and resource requirement differences versus our recommendation and that of CMS.  

• Engaging directly with CMS through formal review and public comment reconsideration processes. 

As a result, CMS reversed its decision, approving a reimbursement rate of $3,800 per test—a fivefold increase. This case study illustrates the need for proactive planning and specialized market access expertise. 

The post Understanding U.S. Market Access: A Foundation for Patient-Centric Success  appeared first on ADRES biopharma regulatory consulting.

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INTERACT Meetings 

The INTERACT meeting is designed for novel products that present unique challenges due to unknown safety profiles, complex manufacturing technologies, or innovative devices. It provides an opportunity for sponsors to obtain initial, non-binding advice from the FDA regarding chemistry, manufacturing, and controls (CMC), pharmacology/toxicology, and early clinical aspects of the development program. This meeting is particularly beneficial when a sponsor has identified the investigational product to be evaluated in a clinical study and conducted some preliminary preclinical proof-of-concept studies but has not yet designed and conducted definitive toxicology studies. 
https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/otp-interact-meetings 

Pre-IND Meetings 

The Pre-IND meeting serves as a platform for sponsors to discuss their development programs and seek regulatory guidance before submitting an IND application. It allows for the review and feedback on the design of preclinical studies, the initial IND study, and product manufacturing and quality controls needed to initiate human studies. This meeting is appropriate when the sponsor has defined the manufacturing process to be used for the clinical studies, developed assays and preliminary lot release criteria, and completed proof-of-concept and possibly some preliminary preclinical GLP safety/toxicology studies. 
https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/otp-pre-ind-meetings 

Key Differences 

• Timing in Development: INTERACT meetings are intended for earlier stages of development, prior to definitive toxicology studies, while Pre-IND meetings are suitable when the development program is more advanced, with defined manufacturing processes and completed proof-of-concept studies. 

• Purpose and Focus: INTERACT meetings focus on obtaining initial advice on early product characterization and preclinical proof-of-concept studies, whereas Pre-IND meetings provide detailed feedback on IND-enabling studies, including CMC, pharmacology/toxicology, and clinical trial design. 

Strategic Considerations for Startups 

Choosing the appropriate meeting type is critical for startups to align their development programs with FDA expectations, optimize resources, and mitigate risks. Engaging in an INTERACT meeting can be advantageous for addressing novel challenges early, while a Pre-IND meeting is beneficial for refining plans as the program progresses toward clinical trials. 

Worth mentioning that FDA may decide, after getting an INTERACT briefing package to advice the company that it is too early for such interaction, meaning that the level and amount of data is not mature enough for such an interaction. While in other cases the FDA will change the format of the meeting to a Pre-IND or a Type C meeting if the sponsor focus is the clinical development of the product.  

Recent FDA Trends 

The FDA has been enhancing its engagement with sponsors through initiatives like the introduction of Type D meetings, which provide a mechanism for addressing narrow questions that can be resolved in a shorter timeframe. Additionally, the formalization of INTERACT meetings reflects the FDA’s commitment to facilitating early communication, especially for innovative products that may present unique challenges. 
 

Conclusion 

For biopharma startups, understanding the distinctions between INTERACT and Pre-IND meetings is essential for effective regulatory strategy. By selecting the appropriate meeting type and engaging with the FDA at optimal stages, companies can enhance their development programs, ensure compliance, and expedite the path to market. 

The post INTERACT vs. Pre-IND Meetings: Navigating Early FDA Pathways for Biopharma Startups appeared first on ADRES biopharma regulatory consulting.

Applicability of U.S. State Privacy Laws to Pharmaceuticals 

U.S. state privacy laws often impose thresholds that many pharmaceutical companies, particularly smaller ones, do not meet. For example, under the CCPA, a business is only subject to the law if it satisfies one of the following conditions: 

• Has annual gross revenues exceeding $25 million. 

• Buys, receives, or sells the personal information of 100,000 or more California residents, households, or devices. 

• Derives 50% or more of its annual revenue from selling personal information. 

Similar thresholds exist in other state privacy laws, including the VCDPA and Colorado Privacy Act (CPA). Smaller pharmaceutical companies, especially those in early stages of development or focused on business-to-business (B2B) operations rather than direct consumer interaction, often do not meet these thresholds. As a result, they are frequently outside the scope of such laws. 

This reality provides a level of relief for many biopharmaceutical firms, enabling them to prioritize compliance with specialized regulations that govern their operations, such as those issued by the U.S. Food and Drug Administration (FDA) and international frameworks like the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice (ICH-GCP) guidelines. 

Exemptions for Clinical Trial Data 

A key factor distinguishing clinical research from other sectors is the comprehensive regulatory oversight that governs the processing of personal data in clinical trials. Most U.S. state privacy laws recognize these existing frameworks and exempt data processed for research purposes under certain conditions. 

For instance: 

• CCPA/CPRA: Excludes personal data used exclusively for scientific, historical, or statistical research in the public interest, provided the research adheres to applicable ethics and privacy laws, such as the Common Rule (45 C.F.R. Part 46), and is overseen by an Institutional Review Board (IRB) or similar entity. 

• VCDPA and CPA: Offer similar exemptions for personal data processed for research purposes that are conducted in compliance with recognized ethical and legal standards. 

• Texas Data Privacy and Security Act (TDPSA): Explicitly exempts identifiable private information collected as part of human subjects research under FDA regulations, ICH-GCP, or the Common Rule. 

These exemptions ensure that data used in clinical trials is governed by a regulatory regime tailored to the unique requirements of clinical research, prioritizing participant safety, data accuracy, and ethical standards. 

A Nuanced Approach to Investigators’ Data 

While data collected about investigators and medical staff is crucial for clinical trial operations, its treatment under privacy laws depends on the context. If this data is processed strictly within the scope of the trial, in compliance with FDA regulations and ICH-GCP, it is typically exempt from U.S. state privacy laws. However, if the same data is used for purposes outside the trial—such as employment-related activities or marketing—and the threshold for application is met, it may fall under the purview of applicable privacy laws. 

Sponsors should exercise caution and limit the processing of investigators’ personal data to the purposes necessary for the trial. Misusing such data outside its intended scope could trigger compliance obligations under U.S. state privacy laws or other applicable regulations. 

Practical Recommendations for Compliance 

Pharmaceutical companies and clinical trial sponsors should take the following steps to ensure compliance: 

1. Assess Applicability: Determine whether state privacy laws apply based on thresholds, business operations, and data processing activities. 

2. Document Exemptions: Clearly document that data used in clinical trials complies with FDA regulations, ICH-GCP guidelines, and ethical standards, demonstrating its exemption from state privacy laws. 

3. Limit Data Use: Restrict the use of investigators’ and staff data to the purposes necessary for trial conduct, avoiding processing for unrelated purposes that could trigger privacy law obligations. 

4. Prepare for GDPR Compliance: For companies running trials in the EU, ensure full alignment with GDPR requirements, including appointing an EU data protection representative, is mandatory. 

Conclusion 

While the growing web of U.S. state privacy laws presents new compliance challenges for businesses, the pharmaceutical and clinical research sectors benefit from tailored exemptions recognizing the rigorous regulatory frameworks already in place. By ensuring that clinical trial data complies with FDA regulations, ICH-GCP, and other applicable laws, sponsors can maintain focus on advancing medical research while respecting data protection requirements, nonetheless, U.S. companies must be vigilant and if conducting trials in the EU, GDPR compliance must be ensured.  

In this evolving landscape, a proactive approach to compliance—rooted in understanding the scope and exemptions of privacy laws—can help pharmaceutical companies navigate complexities and continue driving innovation in clinical research. 

The post Navigating U.S. State Privacy Laws in Clinical Research: Exemptions and Applicability  appeared first on ADRES biopharma regulatory consulting.

One of the earliest determinations you need to make is whether your product will be a consumer-facing or a regulated product, with implications for pathway to market, commercial value, funding, your team, and other strategic matters. 

An illustrative example is a consumer-facing wearable device focused on general wellness that reports on e.g. heartrate or the number of hours you’ve slept in a non-medical setting, that the FDA does not regulate,FN1 in contrast to Continuous Glucose Monitors, or CGMs (even those cleared this year by the FDA for Over-the-Counter, i.e., non-prescription, use), which require at least FDA 510(k) clearance.FN2 

If the intended use and claim for your device is to diagnose or cure, mitigate, treat or prevent a disease, it will be subject to FDA regulation.  While development of an FDA-regulated medical device will require more time, money and clinical data, such a product will typically command a (much) higher price and commercial value. 

Digital therapeutics (or DTx), a category of medical devices that has exploded over the past decade, are software-based medical devices, the use of which are supported by randomized, controlled clinical data to diagnose or cure, mitigate, treat or prevent a disease or condition in a particular patient population.FN3   

Over three dozen DTx products have been approved or cleared by the FDA, for indications in mental health (such as depression, anxiety, schizophrenia, ADHD and insomnia), cardiometabolic diseases (such as diabetes monitoring and treatment), and treatment, prevention of chronic conditions (such as pain), among others.FN4   

FDA’s Center for Devices and Radiological Health (CDRH) regulates DTx as medical devices, technically, as a type of Software-as-a-Medical Device.FN5  Thus, general regulatory considerations, standards and requirements for e.g. Class II 510(k) clearance or Class III De Novo determination, as the case may be, apply.  However, FDA has recognized that software, particularly when combined with Machine Learning/AI that iteratively improves with incremental use via mechanisms such as predetermined change control plans (PCCPs), is different from a pharmacological product, where practically every variation constitutes a new product, necessitating a new safety and efficacy assessment.FN6  The FDA has a Digital Health Center of Excellence that spearheads thinking and policy about digital technologies, including DTx.FN7 Informal inquiries regarding the potential regulatory status of such software products are typically submitted to the Digital Health Center of Excellence’s general mailbox at ﷟HYPERLINK “mailto:DigitalHealth@fda.hhs.gov” for initial agency feedback. 

Regulatory issues are not the only challenges for DTx.  Early leaders stumbled on what observers have characterized as reimbursement and business model issues.  However, the potential of DTx appears undeniable, with next generation approaches that are tackling the challenges,FN8 and Medicare proposing to reimburse for mental health DTx.FN9 Despite these current challenges and in light of the proposed next generation approaches, manufacturers continue to seek clearance for digital therapeutics, especially in the mental health space, where there is a significant need for more at home technologies.  For example, the following additional software devices intended to address mental health conditions have recently been cleared in 2024: 

• MamaLift Plus  – a prescription device intended to treat mild to moderate postpartum depression by improving a patient’s symptoms of depression.FN10 

• Sleepio – a prescription device intended to treat chronic insomnia as an adjunct to usual care.FN11 

• Daylight  – a prescription digital therapeutic intended to treat generalized anxiety disorder by improving a patient’s GAD symptoms as an adjunct to usual care.FN12 

It is important to note that the recent clearances cited above were all supported by robust clinical trials that included a control arm. 

Additional uncertainties have arisen with the returning administration of US President-elect Donald Trump, and his nominees such as Robert F. Kennedy, Jr. to head the Department of Health and Human Services (with oversight over the FDA, the National Institutes of Health, the Centers for Disease Control and the Centers for Medicare and Medicaid Services) and Marty Makary to head FDA, and the recent appointment of Michelle Tarvin as the new CDRH director, after Jeff Shuren’s 15-year tenure.  Crosscurrents such as deregulation and reduction of the administrative state, on the one hand, and greater transparency and safety of regulated products, on the other, portend a period of heightened risks and opportunities for developers of DTx and other rapidly innovating life science products. 

____________  

FN1  See, e.g.:  chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.fda.gov/media/90652/download  

FN2  See, e.g.:  https://www.youtube.com/watch?v=IAJQqQ3oVpE&t=157s) 

FN3 See, e.g.:   https://htdhealth.com/insights/digital-therapeutics-explained/#:~:text=What%20is%20unique%20about%20digital,remove%20the%20health%20provider%20entirely.  

FN4  https://www.nature.com/articles/s41746-023-00777-z#Tab3 

FN5  https://www.fda.gov/medical-devices/digital-health-center-excellence/software-medical-device-samd 

FN6  https://www.fda.gov/regulatory-information/search-fda-guidance-documents/marketing-submission-recommendations-predetermined-change-control-plan-artificial.   

FN7  https://www.fda.gov/medical-devices/digital-health-center-excellence/guidances-digital-health-content 

FN8  See e.g.:  https://pharmaphorum.com/digital/fall-and-rise-digital-therapeutics 

FN9  https://www.statnews.com/2024/07/25/health-tech-news-medicare-dtx-codes-hhs-revamp-fda/  

FN10 K223515.pdf 

FN11 K233577.pdf 

FN12 K233872.pdf 

The post Regulatory and Other Considerations in the Development of Digital Therapeutics  appeared first on ADRES biopharma regulatory consulting.

Why Regulation is Critical for Business Strategy: In digital health, the line between regulated medical devices (e.g., “software as medical device”) and non-regulated software can be thin. Regulatory status influences the business model, time-to-market, and sales strategies. Adhering to regulatory requirements during development prevents costly last-minute changes and accelerates market readiness. 

When to Consider Regulatory Requirements: Regulatory assessments should begin during the initial stages of product planning and development. A detailed understanding of your product’s features, intended use, and indications ensures the viability of the business model and mitigates future hurdles. 

Highly Regulated Environment: The U.S. healthcare sector is extensively regulated, with federal and state laws governing healthcare provision, institutions, professions, and medical data. Tailored regulatory evaluations are essential for compliance and should account for product-specific requirements. 

What to Check 

• Privacy Protection: Privacy compliance is mandatory, especially in healthcare. In the U.S., HIPAA compliance is essential for products involving “covered entities” (e.g., hospital, physicians, clinics) or “business associates” (e.g., a supplier to a covered entity). For business-to-client models, and when HIPAA does not apply, federal and state privacy laws can be relevant. This legislation varies by state, necessitating a thorough review. DNA & biometric data may trigger  specific legislation as they usually attract regulatory attention.  

• Regulatory Authorization: Determining whether your product qualifies as a medical device can impact timelines and costs. Regulatory frameworks for “software as medical device” are evolving, with significant FDA guidance on mobile medical apps, clinical decision-support tools, and AI-enabled devices. Regulatory compliance spans the product’s lifecycle, covering quality control, design, risk management, and labeling. 

• Artificial Intelligence: AI regulation is rapidly developing. While no federal AI law exists in the U.S., hospitals (and other medical institutions) are required by federal law to implement measures aimed at mitigating bias in clinical decision-making tools, and the FDA has issued draft guidance on AI in medical devices and clinical trials. In addition, several states have enacted AI specific state laws that might be relevant. In this period of regulatory uncertainty, adopting AI risk management plans is strongly encouraged to align with emerging standards and best practices, mitigate exposure, meet the expectations of major companies, and attract investor interest. 

• Apps, Websites, and Patient Interfaces: Legal aspects such as terms of use, privacy policies, and informed consent must comply with privacy laws, consumer protection laws, advertising regulations, and disability legislation. Special care is needed for claims about medical benefits and products targeting healthcare professionals. 

• Reimbursement/Insurance: U.S. insurance coverage, known as reimbursement, affects pricing, sales potential, and clinical data requirements. Regulatory approval alone does not guarantee reimbursement, making reimbursement/Insurance expert consultation vital for market entry. 

Additional Considerations: Regulatory choices influence tax planning and Intellectual Property (IP) strategies. For instance, claiming regulatory similarity to existing devices for approval may expose your product to IP challenges. Strategic alignment with regulatory requirements can assist with smoother market integration and long-term success. 

This newsletter is provided for educational purposes only and does not constitute legal advice or legal opinion. Do not act on the information presented without appropriate professional advice after a comprehensive and thorough examination of the specific situation. 

The post Digital Health: Law and Regulation as Part of Your Business Strategy  appeared first on ADRES biopharma regulatory consulting.

This article focuses on the FDA orphan designation program in respect to the incentives offered, the prevalence that defines an orphan disease, as well as the procedural process of obtaining the designation. 

Keywords 

ODD, OMPD, orphan, prevalence, rare  

Introduction 

A rare disease is, as implied, a disease that affects a relatively low number of patients in the population. Many (over 6,000) rare diseases have been identified to date, and it is estimated that 3.5% – 5.9% of the worldwide population is affected by these diseases. 72% of rare diseases are genetic, while others result from infections, allergies, and environmental causes. Due to the low prevalence of each disease, medical expertise is rare, and knowledge and effective care are extensively lacking. In the past, drug manufacturers would not invest in therapies for rare diseases as they could not cover the vast costs of drug development and profit from marketing drugs to such small groups of patients. Despite the urgent need for rare disease¹ medicines, they came to be known as orphans of health systems, as companies would not develop these medicines, and the patient was often denied proper diagnosis and treatment² of therapies for orphan diseases.   

In order to encourage the development, the US Food and Drug Administration (FDA)  launched programs to create financial incentives for developing these therapies. An “orphan designation” is granted for a drug/biologic developed to treat an orphan disease.  

Since their inception, orphan designation programs have successfully created incentives for developing orphan drugs. For example, in 1983, the US Congress passed the Orphan Drug Act (ODA) laid down in 21 Code of Federal Regulations (CFR) §316³ to create financial incentives for orphan drug developers. Since 1983, the Act has resulted in the development of more than 250 orphan drugs, which are available to treat a potential patient population of more than 13 million Americans². 

Orphan Drug Designation in the US 

To be eligible for Orphan Drug Designation (ODD) granted by the FDA, a drug or biologic product should be intended for the safe and effective treatment, diagnosis, or prevention of rare diseases/disorders. To be defined as a rare disease in the US, the disease should affect fewer than 200,000 people in the US (prevalence is <200,000 persons) or affect more than 200,000 persons but not expected to recover the costs of developing and marketing a treatment drug (drugs that will not be profitable within 7 years following approval by the FDA).  

How to Submit a Request for ODD Designation  

An application⁴ of ~30 pages is submitted to the Office of Orphan Products Development (OOPD) by a US representative⁵.  

The basic elements in US FDA orphan designation⁴ application  

• Administrative information 

• Information on the disease or condition: Pathophysiology, etiology, treatment options and prognosis 

• Scientific rationale that demonstrates the drug’s “promise” to treat, diagnose or prevent the disease/condition, e.g., drug description and mode of action relevant to disease/condition; proof of concept studies, in vitro and in vivo data, clinical studies relevant to drug and disease/condition (if available) 

• Regulatory status 

• Determining the population estimate to support that the disease is rare: calculate the number of patients in the US based on established literature references and current US population estimates to show prevalence is < 200,000  

The evaluation process takes a maximum of 90 days from application submission. The application can be submitted on any date.   

The benefits of a US FDA orphan designation  

• Potential 7-year marketing exclusivity after approval 

• Exemption from user fees (waiver of NDA/BLA user fees) 

• Tax credits for qualified clinical testing  

Annual report  

An annual summary of information on the status of orphan drug development should be submitted. These are short documents (~10 pages) submitted between 12 and 14 months from the date of initial designation acceptance annually. The summaries include a review of preclinical and clinical studies performed and planned, a short description of the investigation plan for the coming year, and any anticipated or current problems/difficulties in testing/potential changes that may impact orphan designation.  

Acronyms and abbreviations 

BLA, Biologics License Application; CARs, Cumulative Abnormal Returns; CFR, Code of Federal Regulations; FDA, [US] Food and Drug Administration; NDA, New Drug Application; ODA, Orphan Drug Act; ODD, Orphan Drug Designation; OMPD, Orphan Medicinal Product Designation; OOPD, Office of Orphan Products Development;  

References 

(1) EURORDIS Rare Diseases Europe. What is a rare disease? www.eurordis.org/information-support/what-is-a-rare-disease/ (accessed). 

 
(2) US FDA. Orphan Products: Hope for People With Rare Diseases. 2018. https://www.fda.gov/drugs/information-consumers-and-patients-drugs/orphan-products-hope-people-rare-diseases (accessed). 

(3) US FDA. 21 CFR §316. 2023. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=316 (accessed. 

4) US FDA. Recommended Tips for Creating an Orphan Drug Designation Application. 2018. https://www.fda.gov/media/111762/download (accessed. 

(5) ADRES Ltd. Guiding you through regulatory processes. https://adres.co.il/regulatory-affairs/ (accessed). 

About the authors 

Liron Gibbs-Bar, PhD, is an associate senior regulatory and scientific consultant at ADRES and ADRES EU. She has more than eight years of experience in regulatory affairs, including regulatory strategy, briefing packages, and clinical trial applications writing, as well as interactions with regulatory authorities.  
Dr. Gibbs-Bar has a PhD in developmental biology from the Weizmann Institute of Science. She can be reached at liron@adres.bio 

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*LDTs are in vitro diagnostic products (IVDs) that are intended for clinical use and are designed, manufactured, and used within a single laboratory that is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and meets the regulatory requirements under CLIA to perform high complexity testing. 

Here’s what laboratories need to know and do to stay compliant with Stage One: 

Medical Device Reporting (MDR) Requirements: 
By May 6, 2025, laboratories must comply with MDR regulations, which require reporting to the FDA any adverse events where an LDT may have caused or contributed to a death or serious injury, or if an LDT malfunctions in a way that could lead to harm. Even potential issues (e.g., design flaws or user errors) must be reported. Once a laboratory becomes aware of such an event, a report must be submitted within 30 days (or 5 days for urgent public health risks). Make sure your team establishes robust processes to identify, document, and report these events on time via the FDA’s Electronic Submissions Gateway. 

Correction and Removal Reporting Requirements: 
Labs will also need to comply with the FDA’s correction and removal requirements. Any corrective actions (such as repairs, modifications, or removals) taken to address health risks or unlawful activities related to an LDT must be reported to the FDA within 10 working days. Even if no report is necessary, detailed records must still be kept of all corrections and removals for FDA inspection. Now is the time to set up your system for tracking, documenting, and reporting these activities. 

Quality System Complaint Files: 
The FDA also requires that laboratories maintain formal Quality System complaint files. This means you must have a designated unit to manage and review complaints about your LDTs, ensuring that all complaints—both oral and written—are properly documented and evaluated. If a complaint relates to a potential adverse event, it may trigger additional MDR reporting. Make sure your complaint-handling procedures are solid, with thorough documentation and trend analysis capabilities to ensure compliance during FDA inspections. 

Who Needs to Comply? 

The FDA’s rule applies to most laboratories offering nonexempt LDTs. Some exceptions exist, such as: 

1. LDTs similar to those used in 1976, performed manually in a single CLIA-certified laboratory. 

2. LDTs used for human leukocyte antigen (HLA) testing in transplant activities. 

3. Forensic tests for law enforcement purposes. 

4. LDTs manufactured and used within the Department of Defense or Veterans Health Administration. 

However, if your laboratory offers any LDTs outside of these categories, it’s time to ensure compliance with the FDA’s Stage One requirements. 

Why Prepare Now? 

While there are ongoing legal challenges to the FDA’s authority over LDTs, including lawsuits from the American Clinical Laboratory Association (ACLA) and other groups, labs should not wait for these cases to be resolved before acting. It is unclear if the courts will rule before the May 2025 deadline, and waiting could lead to last-minute infrastructure investments and rushed compliance efforts. 

Setting up the necessary infrastructure for adverse event reporting, correction and removal systems, and complaint handling processes will take time. Start assessing your laboratory’s current capabilities now and develop an action plan to ensure you’re ready to meet these new regulatory obligations. 

Next Steps: 

1. Assess compliance needs: Evaluate whether your LDTs are exempt or subject to Stage One requirements. 

2. Implement reporting systems: Set up the processes and technology needed to meet MDR, correction, and removal obligations. 

3. Establish complaint procedures: Designate and train a formal complaint unit, and develop comprehensive documentation practices. 

4. Stay informed: Keep an eye on the evolving legal landscape and any updates from the FDA or courts that could impact your compliance timeline. 

The FDA’s rule represents a major shift for the industry, and the deadlines are approaching fast. Now is the time to get ahead of the curve and ensure your laboratory is fully compliant by May 6, 2025.  

The ADRES team is here to support you in ensuring your laboratory achieves full compliance with the latest FDA regulations.

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