Recognizing that the fundamental mechanisms of partial onset seizures (POS) are similar across age groups, the FDA established the guidance, Drugs for Treatment of Partial Onset Seizures: Extrapolation of Efficacy from Adults to Pediatric Patients 1 Month of Age and Older. In this blog post, we discuss the key components of the guidance and the impact it has on streamlining the approval process for pediatric patients.  

Regulatory background: Addressing a critical need 

Historically, the FDA, based on the US Federal Food, Drug and Cosmetic Act, required sponsors to establish efficacy for the treatment of POS in pediatric patients by performing one or more adequate and well-controlled clinical studies in pediatric patients using doses adjusted based on body weight and age. This was due to the lack of evidence supporting extrapolation of efficacy and safety information obtained in adult patients to pediatric patients. 

In the new guidance, however, the FDA describes an approach where efficacy can be extrapolated from adults to pediatric patients when it is reasonable to assume that children, compared with adults, have a similar: 

• Progression of disease, 
• Response to treatment; and,  
• Exposure-response relationship. 

The FDA developed this innovative extrapolation approach after conducting systematic and quantitative analyses of historical clinical data on drugs with various mechanisms of action approved for treating POS in both adults and pediatric patients. The findings revealed a consistent relationship between drug exposure and response (reduction in seizure frequency) across age groups, extending to pediatric patients as young as 1 month old due to their phenomenological and pathophysiological similarity. This evidence allowed the FDA to conclude that the efficacy of drugs approved for the treatment of POS can be reliably extrapolated from adults to pediatric patients. 

Other regulatory approaches  

It is worth noting that the European Medicines Agency (EMA) has also established guidelines that allow for the extrapolation of efficacy data from adults to pediatric patients in the treatment of POS. Like the FDA guidance, the EMA’s “Reflection Paper on the Use of Extrapolation in the Development of Medicines for Paediatrics” outlines a framework for extrapolating efficacy and safety data from adults to children. However, the EMA’s extrapolation policy applies to children aged 4 years and older⁴, versus the FDA’s recommendation of patients as young as 1 month old. 

Both agencies aim to facilitate the availability of effective treatments for pediatric patients by reducing the need for extensive efficacy trials in children, focusing instead on safety and pharmacokinetic assessments. 

Applications of the FDA guidance in POS drug development  

Formulation development 

Developing drugs for children presents unique formulation challenges compared to those for adults. It is important to create age-appropriate formulations tailored to different pediatric age groups. This includes developing child-friendly dosage forms that ensure palatability, ease of administration, and precise dose delivery. 

Efficacy considerations 

Since the FDA’s efficacy extrapolation conclusion applies only to partial-onset seizures (POS), sponsors may consider using validated exposure-response models (e.g., PK/PD models) to predict drug concentrations and treatment response (such as seizure reduction) for other types of seizures. These models utilize virtual patient populations to support efficacy extrapolation in pediatric patients. 

Clinical pharmacology and dosing  

To support extrapolation, sponsors should collect blood concentrations of active drugs and metabolites in an adequately designed pharmacokinetic and tolerability study in patients 1 month to 16 years of age. These studies are designed to characterize acute tolerability over a range of doses that covers drug concentrations known to be effective in adults.  

Importantly, pharmacokinetic simulations should be performed to aid in the selection of doses expected to achieve therapeutic exposures similar to adult exposures. Sponsors should discuss simulation results with the FDA before initiating safety studies.   

Safety  

The FDA expects sponsors to conduct clinical trials to assess the safety of the drug in pediatric patients aged 1 month and older with partial onset seizures, ensuring that all age groups are adequately represented. These studies may be open-label, with a minimum of 100 pediatric patients exposed to the drug for at least 6 months. Dosing levels in safety studies should match those found to be effective in the pediatric population based on extrapolation methods using adult drug exposures, as outlined in the guidance. Dose selection and optimization can be done by simulating proposed doses using the validated exposure-response model. 

Looking ahead 

The FDA’s decision to allow efficacy extrapolation marks a pivotal moment in pediatric seizure treatment. By eliminating the need for separate pediatric efficacy trials, the approval process for anti-seizure medications can be accelerated, allowing young patients to access new treatments sooner. This shift in focus also ensures that while medications reach the market more quickly, they remain both effective and safe for children. 

Further, removing the requirement for large-scale efficacy trials in young children addresses ethical and logistical challenges. It reduces concerns associated with recruiting pediatric participants for placebo-controlled studies, making pediatric drug research more feasible and patient-friendly. 

Premier Research has extensive experience in supporting the development of exposure-response models, optimizing the pathway to a safe and efficacious dose, and conducting clinical trials in the epilepsy space. For support with your program, contact us.  

ABOUT PREMIER RESEARCH:  

Premier Research, a global clinical research, product development, and consulting company, is dedicated to helping innovators transform life-changing ideas and breakthrough science into new medical treatments. We offer strategic solutions across the entire development lifecycle, from pre-clinical through commercialization, specializing in smart study design and full-service clinical trial management.    

Leveraging technology and therapeutic expertise, we deliver clean, conclusive data with a focus on reducing development timelines, securing access to the right patients, and effectively navigating global regulations to ensure submission-ready results.    

As an organization that puts patients first, we pride ourselves on helping customers answer the unmet needs of patients across a broad range of medical conditions. Visit prmresearch.com.  

[1] Epilepsy Foundation, https://www.epilepsy.com 

[2] NIH, National Library of Medicine, Partial Epilepsy – StatPearls – NCBI Bookshelf 

[3] NIH, National Library of Medicine, Epilepsy and Seizures | National Institute of Neurological Disorders and Stroke 

[4] EMA,2016. Reflection paper on extrapolation of efficacy and safety in pediatric medicine development  https://www.ema.europa.eu/en/extrapolation-efficacy-safety-paediatric-medicine-development-scientific-guideline 

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To find out more, we sat down with Premier’s Senior Vice President and Global Head, Biometrics, Abie Ekangaki, Ph. D., for an engaging conversation about this innovative approach to drug development. 

Abie, for those who might be less than savvy in in silico methodologies, can you describe what in silico modeling is? 

In the simplest terms, you can think of in silico as a way to generate or produce something using computer modeling or computer simulation, and that’s it. It’s worth noting that one can apply in silico modeling in a broad array of situations, and it simply involves the use of mathematical or computational models that can replicate actual real-world phenomena.  

A unique benefit of in silico predictive modeling of the molecular dynamics and system biology, for instance, is that it can eventually yield a digital rendition of an entity that mimics the biological conditions associated with a particular disease. In other words, it can yield a digital rendition of a patient having a specific disease. This is the area where in silico methods can truly be groundbreaking. And I believe that as in silico modeling and simulation methods evolve, it will eventually transform the future of drug development. 

Is in silico modeling a new concept in clinical research? If not, what is driving the recent interest and focus in the industry? 

It’s important to understand firstly that in silico modeling and simulation is just one application of machine learning techniques. And machine learning methods in general represent only a sliver of the much broader and more sophisticated world of artificial intelligence (AI). We know that for years, AI has been transforming industries by automating tasks, enhancing decision making, and creating new value.  

The drug development space has been slower and more conservative in its adoption of these approaches, particularly when it comes to securing regulatory agency endorsement of these methodologies for driving regulatory decisions. We’re seeing recent trends, however, where both the FDA and EMA are more open to leveraging in silico modeling and simulation techniques in clinical trials for drug approval. In fact, in a 2020 press announcement, the FDA commissioner at the time, Scott Gottlieb, shared that in silico methods are recognized by the FDA as a useful tool for streamlining randomized control trials and advancing personalized treatment. 

The following year, FDA’s internal modeling and simulation group released a report which outlined its successes and opportunities in modeling and simulation. The report revealed the extent to which CDER, the Center for Drug Evaluation and Research, had already been actively implementing these techniques in PK modeling, Bayesian modeling, and in disease modeling, among other areas. All of this demonstrates FDA’s recognition of, and commitment to, the inevitable role of complex modeling and simulation techniques, which will continue to be the case in the drug development process. And I believe this is what contributes to the growing interest around in silico modeling and simulation in the industry.  

Are there particular therapeutic areas or indications where in silico modeling is preferred? 

There is currently no clear guidance from FDA around restricting in silico modeling and simulation approaches to specific therapeutic areas. For now, we know anecdotally that it depends on the area of application of these in silico techniques.  

For example, in silico methods used for PK/PD modeling are generally disease or therapeutic area agnostic. However, when using these methods for disease mechanistic modeling, which is a unique approach that leads to generating synthetic patients for use as control arms in clinical trials, the FDA is generally more likely to favor in silico approaches for rare and ultra rare diseases, particularly where there are no available treatments or perhaps little available real-world data that can adequately serve as a control arm for efficacy evaluation. In these cases, it may also be unethical to assign patients to a placebo, like in pediatric glioblastoma trials. 

In contrast, it’s most unlikely that the FDA would accept in silico synthetic controls in situations where there is no justifiable clinical reason why human subjects cannot be issued a placebo or active control in a clinical trial, such as in pain or diabetes studies. As a general rule of thumb, I always recommend that sponsors engage the FDA in discussions of trial design options for their proposed study, especially when more complex in silico methods are being proposed.  

There is a notion that in silico trial designs can lead to early conditional approval of a new drug. Can you outline how this is achieved? 

A strategic benefit of in silico modeling and simulation methods is that they can circumvent or condense key stages of the drug development process that would result in significant reduction in the development time and cost. There are several success stories where applications of in silico methods have received FDA endorsement to progress towards a conditional approval. In fact, computational modeling and simulation has been incorporated into pre-market approval applications for medical devices as far back as 2002. In 2023, a Hong Kong-based AI drug discovery company called Insilico Medicine succeeded in securing orphan drug designation from the FDA for a small molecule developed for idiopathic pulmonary fibrosis. Excitingly, the company developed their drug candidate purely using in silico AI modeling and simulation.  

Another recent example is the COVID vaccine trials of 2021. In silico modeling and simulation was applied in the rush for a vaccine by conducting virtual trials to assess the efficacy prospects of proposed vaccine candidates. These computational methods directly led to the selection of the optimal treatment option or optimal vaccine candidate that was then moved forward for confirmatory evaluations in the single pivotal human trials that the likes of Pfizer and Moderna conducted. Without doubt, the implementation of complex in silico modeling and simulation techniques for those vaccine trials had a transformational impact in precipitating the drug development process and achieving vaccine approval within one year.  

Can you expand on the appetite for in silico modeling amongst regulatory bodies? Is this method generally accepted or is there work to do on that front? 

Both the FDA and EMA have encouraged the implementation of complex modeling and simulation techniques in support of the design, analysis and reporting of clinical trials. In fact, in December 2020 the FDA published its regulatory guidance on complex innovative designs for drugs and biologics. This guidance has since set the framework for how sponsors may obtain FDA feedback on technical issues related to modeling and simulation in their trials. And this guidance has also made quite clear the type of quantitative and qualitative information that support these approaches and which sponsors should submit for FDA review.  

Four years later, in silico modeling and simulation applications have become even more sophisticated, largely due to advancements in technology and computational power, and are delving into areas like generating synthetic patients, digital twins, etc. In my view, more work is needed by regulatory agencies to update current guidance that addresses regulatory expectations for the increased sophistication of the modeling and simulation techniques.  

However, we can see that work is ongoing to strengthen and refine expectations. Earlier this year, the Avicenna Alliance, an international consortium of more than 130 experts in the industry, academia, and regulatory agencies, including 13 FDA modeling and simulation working group members, released a comprehensive publication, which they titled Toward Good Simulation Practice. This publication offers the first comprehensive compilation of good practices for ensuring the quality and reliability of computational modeling and simulation in the assessment of medical products.  

How do you foresee the clinical trial industry evolving as in silico modeling becomes more widely adopted? 

In a funny way, I still remember 1999 when there was stupendously wild speculation globally about how the world will suddenly change once we enter the new millennium. But what did we find? All the anxiety was completely unwarranted. I think something similar will happen here. In the short-term, I don’t foresee any dramatic transformation in how clinical trials are conducted. Rather, I expect to see gradual enhancements and efficiencies across the drug development process over the next decade, with innovative modeling and simulation approaches playing an important part in that.  

I expect that for some diseases, in silico modeling will help reduce the burden of requiring human subjects, or they may even circumvent the need for traditional early phase human trials in some instances. I also believe these approaches will help boost the speed of bringing drugs to market, particularly for certain types of diseases that are better positioned to satisfy regulatory requirements for more innovative approaches.  

There is much more work needed for developing technical skills, expertise, and for building more sophisticated computational systems that are readily accessible and used for highly complex dynamic AI modeling and simulation. We are entering an inflection point today, but it’s incumbent on those of us who are knowledgeable in this space to raise awareness of what’s possible with innovative in silico methods, and to help enlighten investigators and sponsors on how regulatory bodies have embraced such innovation.  

You’ve been a biostatistician for over 30 years and have seen lots of changes in the space. What excites you most about innovative methodologies like in silico? 

I will unabashedly modify a famous quote by saying this, “the beauty of progress lies not in reaching the end, but in the continual refinement of our tools and understanding.” Having said that, when I think about where we are today and compare it to when I first became a professional biostatistician in 1989, there’s no doubt in my mind that we are in an exciting era of innovative statistical methodologies, where the methods we bring to the table can have major impact in bringing needed medicines to patients faster. In fact, one can arguably say that today we’re standing at the threshold of new truths where uncertainty is not a limitation, but instead an invitation to discovery. So yes, these are indeed exciting times to be a biostatistician or a data scientist, but I would say more importantly, these are exciting times in the drug development space.  

___ 

To hear more of Abie’s perspectives and expertise around in silico modeling and simulation, book a meeting with him here. 

The post In Silico 101: Interview with Seasoned Biostatistician on Accelerating Drug Development   appeared first on Premier Research.

Regulatory Pathway 505(b)(2) versus 505(b)(1)

In the US, novel new small molecule drug products, including some peptides, are regulated, and approved by the FDA under the Federal Food, Drug, and Cosmetic Act (the “Federal FD&C Act”) under two key regulatory pathways: Section 505(b)(1) and Section 505(b)(2) NDAs. A key difference is that the Sponsor of a 505(b)(1) NDA owns or has right of reference to the safety and effectiveness information versus the Sponsor of a 505(b)(2) NDA leverages information from other drug approval packages and/or published information they do not own or have right of reference to. Typically, new drug development under 505(b)(1) pathway requires significant capital and time and has lower success rate versus the 505(b)(2) pathway, which leverages existing drug approvals and publicly- available scientific information.   

Clinical Pharmacology in Drug Development

Clinical pharmacology in drug development covers all aspects of interaction between humans and drugs. Clinical pharmacology studies include both in vitro studies using human biomaterials and in vivo human studies and are focused on characterizing pharmacokinetics (PK) (e.g., absorption, distribution, metabolism, and excretion (the ADME properties) – what the body does to the drug), pharmacodynamics (PD) (what the drug does to the body; both the desired drug activity and the adverse effects) and PK/PD relationships of the drug. Clinical pharmacology also includes an evaluation of the impact of intrinsic factors (e.g., age, gender, race/ethnicity, genomics, and organ dysfunction) and extrinsic factors (e.g., food effect, smoking, and drug-drug interactions) on drug exposure and response.

Clinical Pharmacology Programs Under 505(b)(1) Versus 505(b)(2) Pathways

Drug product approval via the 505(b)(1) pathway requires a full assessment of clinical pharmacology aspects including the Mechanism of Action (MOA), ADME properties, characterizing single dose and multiple dose PK and PD, evaluation in specialized populations like geriatrics, renal and/or hepatic impairment, drug-drug interactions, potential for QTC prolongation, PK/PD effect.  

In addition to more traditional clinical pharmacology approaches, Model Informed Drug Development (MIDD) is now being used to tailor clinical pharmacology development, leading to potential reductions in overall clinical programs and higher success rates. For example, PK and PD information generated in early phase development is integrated in population modeling techniques which guides late phase development, such as choosing a dose and dosing regimen that has the high probability of demonstrating efficacy while reducing side effects. In another example, physiological based PK modeling can be used to characterize drug-drug interaction potential without conducting specific clinical studies. These modeling techniques can help to reduce the size and duration of the overall clinical pharmacology program.

In contrast to 505(b)(1) programs, the 505(b)(2) pathway provides added flexibility and typically reduces the overall clinical pharmacology program based on successful bridging to previously approved product(s) (i.e., Listed Drugs [LDs]) and/or published scientific literature. Like 505(b)(1) programs, MIDD approaches can be utilized to justify any PK differences that do not affect PD or efficacy, apply for a biowaiver, etc. and reduce the overall clinical pharmacology program.

The following table compares the clinical pharmacology programs under the 505(b)(1) and 505(b)(2) pathways.

Case studies

In this section, we present two case studies in which strategic clinical pharmacology decisions were made that helped to expedite our Clients’ clinical development programs.

505(b)(1) case study:

A Sponsor was close to submitting an NDA for their New Chemical Entity (NCE) under the 505(b)(1) pathway and asked Premier to conduct a readiness assessment. Premier clinical pharmacology experts determined that a renal impairment study and a Thorough QT (TQT) study were needed for the NDA. Premier was able to avoid these two key clinical studies by conducting PK/PD modeling to determine dose adjustments in renally impaired subjects and a Concentration-QT (C-QT) analysis to demonstrate that the NCE was unlikely to cause cardiac effects, which supported a successful TQT waiver.

505(b)(2) case study:

In a comparative bioavailability PK bridging study, the Sponsor’s product (an extended-release product) and the LD (immediate release product) were not bioequivalent. The area under the curve (AUC) for both products were bioequivalent but the rate of exposure (C_max and T_max) was dissimilar. Premier experts used MIDD to tailor the clinical development program using a comparative PK/PD approach to build a scientific bridge between the Sponsor’s product and the LD despite the lack of bioequivalence. This provided a scientific bridge to the LD’s safety and efficacy information and avoided additional and costly clinical efficacy and safety studies.

Conclusions

MIDD can be used in both 505(b)(1) and 505(b)(2) clinical pharmacology programs to reduce the size of the programs and expedite development by avoiding costly clinical studies.

Accelerate Drug Development with the Right Partner

As we have discussed, the assessment of clinical pharmacology in drug development programs includes multiple aspects and approaches vary from product to product. Each drug development program is unique but there are opportunities to be strategically creative to reduce the size and time to market in both 505(b)(1) and 505(b)(2) programs. It is important to work with a partner with experience and who recognizes these opportunities. Leverage our team’s expertise and holistic approach for streamlining and accelerating your clinical programs and addressing critical clinical issues, contact us.

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Background

A harmonized approach to assessing DDI is long overdue. Until now, regulatory guidance has been agency-specific with variations in recommendations and expectations. The US Food and Drug Administration (FDA) has two main DDI guidances, published in 2020, one for in vitro studies and one for clinical DDI studies. The European Medicines Agency (EMA) has their own guidance finalized in 2013 and so does Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), finalized in 2018. ICH M12 consolidates DDI recommendations from all three regulatory agencies, providing a consistent approach in designing, conducting, and interpreting in vitro and clinical DDI studies during the development of a therapeutic product in order to facilitate patient access to needed therapies and streamline global drug development.

Highlights

• ICH M12 is a comprehensive guidance on pharmacokinetic DDI, covering both in vitro and clinical DDI study recommendations and designs, with a focus on enzyme- and transporter-mediated interactions.
  • It also includes lists of recommended substrates and inhibitors for both in vitro and clinical DDI studies which is not included in the FDA guidances.
• Important timelines for when to conduct in vitro assays in relation to the clinical drug development program.
  • ICH M12 outlines which in vitro DDI studies/assessments should be available prior to initiation of each clinical phase.
  • There was minimal guidance on timing in the FDA guidances, more information was provided in the EMA guidance.
• The new guidance contains a discussion of DDI considerations for protein therapeutics, such as considering implications on P450 activity if cytokines are modulated and about studies appropriate for antibody-drug conjugates.
  • These are similar to that discussed in FDA’s therapeutic protein guidance but was not addressed in the FDA’s in vitro DDI guidance.
• Phase II glucuronidation enzymes got a special shoutout; in the FDA’s in vitro DDI guidance, there was minimal guidance on the evaluation of UDP-glucuronosyltransferase enzymes.
  • ICH M12 provides a detailed discussion of when to evaluate UDP-glucuronosyltransferase enzymes and a list of recommended substrates and inhibitors to use for in vitro and clinical studies.
• Clarity on when to evaluate metabolite DDI:
  • As a substrate: In ICH M12, considerations for evaluating DDI of metabolites is consolidated, as in FDA’s in vitro DDI guidance. The recommendation remains the same as in previous guidances: the metabolite’s role as a substrate for metabolic enzymes and transporters should be investigated if there is data suggesting changes in metabolite exposure may affect efficacy or safety. In vitro studies should also be conducted if the metabolite has in vivo pharmacological effects similar to or greater than the parent compound.
  • As an inhibitor: The metabolite’s ability to inhibit metabolism and transporters should be assessed if the AUC_metab ≥ 25 % of the AUC_parent and accounts for at least 10% of drug-related material in circulation (ie, considered a major metabolite per ICH M3). In vitro studies may not be needed if clinical DDI studies that can capture the DDI potential of the metabolite are planned. This change is more consistent with the approach in the EMA guidance.
  • As an inducer: Induction studies of the metabolite are typically not needed as they are evaluated in assays with the parent drug. If the metabolite is formed extra-hepatically, then in vitro evaluation of the metabolite is recommended using the same threshold as for inhibition. Previously, the FDA guidance did not specify assessment of metabolites as inducers.
• Clinical DDI recommendations in ICH M12 generally parallel FDA’s previous clinical DDI guidance. ICH M12 discusses various aspects of clinical DDI studies, including:
  • Study design (eg, standalone vs nested design, crossover vs parallel)
  • Study population (eg, healthy volunteers vs patients)
  • Dose and dose regimen of study drug (eg, timing of administration, co-medications)
  • Index substrates
  • Assessing influence of pharmacogenetics
  • Route of drug administration
  • Model-informed drug development approaches (eg, population PK models, mechanistic static)
  • Study reporting and interpretation
• ICH M12 also provides risk assessment and management considerations that are critical in the clinical development program.
  • Risk assessment should inform the use of DDI management strategies that will evaluate how clinically relevant concomitant use of the drugs leads to safety, effectiveness, or tolerability concerns compared to those present when the drugs are administered alone.

What This Means for Your Program

The ICH M12 guidance provides a one-stop shop for understanding how to evaluate DDIs during drug development. Make sure your drug development plan/program is in line with the latest recommendations: Are you evaluating the most appropriate P450 enzymes and transporters using the latest thresholds? Do your metabolites need to be evaluated for DDI? Is your DDI risk mitigation plan appropriate? How can the recommended approaches be leveraged to optimize your drug development program? How can you incorporate model-informed drug development into your clinical program with the relevant clinical DDI considerations? How do the recommendations in this guidance apply to your 505(b)(2) program? Our experts at Premier can help you identify what DDI approach your program needs to be up to date with regulatory expectations to achieve your corporate goals.

The post The New Drug-Drug Interaction Guidance, ICH M12: How to Accelerate Your Drug Development Program appeared first on Premier Research.

A Pre-Investigational New Drug Application (pre-IND) meeting can be a valuable component in planning a development program. For companies that have not previously interacted with the FDA in the early stages of a product’s development, a pre-IND meeting is an opportunity to receive the Agency’s feedback and guidance. While FDA guidance documents can provide helpful information, they are broadly applicable to several types of products. Through a pre-IND meeting, a sponsor can get the Agency’s unique advice for a specific product.

Interacting with the Agency early in a development program can reduce time to market in several ways:

• Identifying and avoiding unnecessary studies
• Ensuring that necessary studies are designed to provide useful information
• Gaining FDA support for a proposed strategy
• Minimizing the potential for a clinical hold
• Providing an opportunity for the creative exchange of ideas
• Obtaining regulatory insight
• Minimizing costs
• Clearly defining the endpoints and goals of the development program

Given these advantages, it is always advisable to seek the FDA’s guidance early in a drug’s development. The first step is to prepare a pre-IND (or PIND) meeting request submission with the questions for the FDA to answer. Asking the appropriate questions is critical because the FDA uses information in the request letter to determine (a) if a face-to-face or teleconference meeting or written responses should be granted (or denied) and (b) which reviewers will be at the meeting to facilitate a productive discussion.

The key to a successful pre-IND meeting is getting clarity from FDA reviewers on what development activities are necessary to work toward NDA approval. This clarity allows the sponsor to estimate the cost, duration, and potential risks of the program and is especially important for complex development programs. To gain this understanding, sponsors must ask the right questions in the right way.

Be Clear and Specific

When questions are clear and specific, FDA reviewers will be more likely to provide meaningful and helpful recommendations.

Questions should be direct, clearly stated, and posed in a such a way that FDA reviewers can either agree or disagree with a proposed plan. A brief explanation of the planned study or strategy should be included (typically prior to asking the question). For example, a sponsor might explain its proposed comparative bioavailability study for a 505(b)(2) development program and then ask the following question:

Does the Agency agree that the proposed approach, if successful, will establish a clinical safety bridge to Listed Drug Z?

This question would likely receive a clear answer from the FDA if the sponsor also presents a detailed plan or proposal. Conversely, if the proposal is too general or ambiguous, or if the question is open-ended, FDA reviewers may not be able to agree with the study design or to provide useful recommendations for the plan. We recommend not asking questions like these:

What sponsor-conducted nonclinical studies does the Agency recommend to support opening an IND?

The sponsor would like to support the safety of Product A by referencing safety information available from the labeling of an approved drug product. What listed drug does the Agency recommend for the sponsor’s development program?

Do the Research

Ensure that the questions are credible from a scientific and regulatory perspective.

It is important to review all relevant reference information—from FDA websites, guidance documents, and precedents set by recent product approvals—prior to deciding on a drug development plan. This way, a sponsor can ensure that the questions are well-informed and in line with FDA regulations and guidelines. Where possible, a sponsor should support the rationale of proposed plans or studies with data from its own studies or strong evidence from published studies. Providing FDA reviewers with supportive scientific evidence increases the chance of obtaining agreement or helpful feedback.

Choosing not to take the time to understand regulatory guidelines before proposing a plan may backfire. Here’s an example:

A sponsor is planning to develop ABC-101, a topical ointment with Drug X as the active pharmaceutical ingredient, to treat a chronic skin condition. Drug X has been approved as an ointment and the sponsor learns about Listed Drug Z, a topical ointment indicated for use during ophthalmic surgical procedures. The sponsor decides to rely on the safety information available from Listed Drug Z to support the safety of its product, based on information presented in the LD’s approved labeling. The sponsor decides to ask the FDA the following questions:

Does the Agency agree that the proposed 505(b)(2) approach, including reliance on Listed Drug Z (ophthalmic ointment), is appropriate for review of the ABC-101 NDA?

The sponsor is planning to rely, in part, on the Agency’s previous findings of safety for Drug X, as referenced in the approved labeling of Listed Drug Z. Does the Agency agree with this approach?

While these questions are clear and targeted, the Agency would likely not agree to this approach because the LD is not appropriate for the proposed product. Unlike Listed Drug Z, which is intended for acute use during ophthalmic surgery, ABC-101 is intended for chronic use. Thus, the safety information from the LD would not be sufficient to support the safety of the product.

This example illustrates the importance of doing the research to ensure that the strategies and plans proposed are scientifically and regulatorily sound.

Consider All Aspects of Drug Development

Do not limit questions to the early stages of a program.

The pre-IND meeting is an opportunity to discuss development plans from the pre-IND stage up until submission of an NDA. This includes gaining agreement or advice on a program’s integral chemistry, manufacturing, and controls (CMC) components and pivotal nonclinical and clinical studies to avoid unnecessary delays and costs.

Here are some examples of the types of questions to consider asking:

Does the Agency agree that the sponsor-conducted nonclinical studies are sufficient to enable the proposed clinical development program?

Does the Agency agree that the clinical pharmacology information in the LD labeling, in conjunction with the PK data for the sponsor’s product, is sufficient to fulfill the clinical pharmacology requirements for the NDA?

Does the Agency agree that a control strategy based on the outlined drug substance and drug product quality attributes will be sufficient to support the identity, potency, purity, quality, and stability review of the drug substance and the sponsor’s drug product?

Giving FDA reviewers a chance to understand the overall plans for developing a product will ensure that the necessary studies are designed to provide the most useful information, an approach which could minimize the costs and potential risks of a development program.

For additional details on how to have a successful pre-IND meeting, check out Premier Consulting’s blog post titled Pre-IND Meetings: How to Achieve Success for 505(b)(2).

If you are in the early stages of your product’s development and considering a pre-IND meeting, contact us to learn how we can help you map out a strategic development plan to enable a successful and productive interaction with the FDA.

The post Three Keys to Preparing Effective Pre-IND Meeting Questions appeared first on Premier Research.

Can you identify a safe AND efficacious clinical dose?

As in all nonclinical drug development programs, the goal is to identify potential safety issues in humans. Prior to clinical trials, the focus is typically on evaluating safety. However, for cell and gene therapy products, the nonclinical program needs to identify a clinical dose that is likely both safe AND efficacious. This is due to the high-risk nature of these kinds of products (especially for a first-in-class therapy) and the fact that some cell or gene therapies can only be administered once due to the development of immune responses to the drug product. Thus, it is ethically necessary to administer a dose that has a potential to be safe but also efficacious. The doses assessed in the nonclinical program should bracket anticipated clinical exposures, ranging from the minimal effective dose to a maximum therapeutic dose that ideally provides a margin of safety. 

Is fit-for-purpose?

Cell and gene therapies often have been designed to have unique biological activity, typically towards a human-specific target. Thus, while the same types of safety endpoints need to be evaluated, the studies done to do so often look different compared to those for a small molecule. To ensure that all aspects of safety are adequately assessed, it is important for the Sponsor to design fit-for-purpose studies that will provide the most relevant information using all the available knowledge about the therapeutic, biology, cross-species reactivity, and disease mechanisms.

Pharmacology and toxicology studies may need to be done in a humanized animal model or a species-specific surrogate product (e.g., target species version of a gene) to evaluate primary and secondary pharmacology. If there is one or no pharmacologically relevant species, toxicity assessments may be limited to one species instead of two. Traditional genotoxicity studies looking at potential for direct gene mutations are typically not appropriate due to the mechanism of action and/or biology; rather, genotoxicity is assessed through other mechanisms, such as by evaluating the potential for insertion of gene sequences into the genome or monitoring genetic modifications in target and non-target tissues. Immunotoxicity of the drug product often needs to be assessed due to the immunogenic nature of cell and gene therapies; these include measuring for anti-drug antibodies or T-cell reactivity to vector components, transgene, and/or gene product.

Does it have input and buy-in from regulatory agencies?

Due to the rapidly evolving nature of research and development in cell and gene therapies, new information from basic research or on-going clinical trials are constantly being evaluated by regulatory agencies to inform their evaluation of incoming Investigational New Drug applications (INDs) or Clinical Trial Applications (CTAs). Thus, it is of upmost importance to seek out regulatory input early and often particularly for cell or gene therapies to get the most up-to-date advice. In the US, the FDA offers early engagement through INTERACT meetings where preliminary proof-of-concept data can be discussed as well as pre-IND meetings for more advanced programs where the discussion centers on IND-enabling toxicity studies. The requirement for information (e.g., viral shedding) can vary by regulatory authority so it is good to initiate those conversations to ensure a smooth and timely transition into clinical trials.

The cell and gene therapy space is exciting and impactful. Premier has capabilities to support these innovative products from early nonclinical development to clinical trial implementation, combining CGT-specific expertise from toxicologists, chemists, biologists, regulatory managers, and clinical researchers. Contact us today to learn more about how Premier can support your next cell and gene therapy program.

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In which species should the toxicity study be conducted? Does it have to be in a disease model?

The cell or gene therapy should be pharmacologically active in the animal model. If the target is only active in a disease state, then efficacy and safety studies may need to be conducted in the disease model. If this is the case, consider collecting both efficacy and safety endpoints in the same study to reduce the use of animals. If the compound is not active in any species (e.g., human-specific gene target), a surrogate molecule could be used. Note that there is no strict requirement of toxicity studies in two species, which is often needed for small molecule programs.

Do you have a unique or novel route of administration (RoA) (e.g., surgical procedure, intracerebral)? If so, consider using an animal species that will accommodate that RoA or provide a way to best mimic that RoA.

In the end, the data generated needs to provide biologically relevant information about how the therapy will behave in humans. Provide justifications for the species used and understand the limitations of each model and how data from animal studies translate to humans. These will be important to outline clearly in the Investigational New Drug application (IND) or Clinical Trial Application (CTA).

How long does the study need to be?

Acute and delayed toxicity should be evaluated in safety studies. Thus, it is important to know the kinetics of your therapy (e.g., how long does it stay in the body, how long is it active, when is peak expression). Then, build in timepoints into the safety study to provide meaningful data on potential toxicity. For example, evaluate acute toxicity at the peak of activity, delayed toxicity at a timepoint where there is steady state of expression/activity, and, if needed, recovery at a timepoint that provides enough time for recovery, taking into consideration the rate of clearance of therapeutic or cessation of activity.

What endpoints need to be evaluated?

Toxicity studies should strive to evaluate all typical general toxicity endpoints (e.g., clinical observations, clinical pathology, histology). In addition, immunogenicity endpoints (e.g., anti-drug antibodies, cytokine production, T-cell response to vector and transgene) are also typically needed to understand the body’s response to the therapeutic. Biodistribution of the product (transgene/gene or cells) should be evaluated. Remember to consider if clinical data on similar therapies can help inform target organs or reactions to monitor for in your studies.

Consider including vector shedding (e.g., in feces or urine); though there is a discrepancy between some regulatory agencies, it seems that the field is moving in the direction of expecting vector shedding data, so it is best to collect the samples just in case.

The need for safety pharmacology, genotoxicity (in the form of evaluating potential for integration), reproductive toxicity, and tumorgenicity should be assessed based on the target indication and nature of the therapy. For example, if there is no biodistribution to reproductive organs, then conducting reproductive toxicity studies may not be needed.

What doses should I use for safety studies?

The nonclinical program for cell or gene therapy products should identify a potentially efficacious dose and ideal dose regimen for the proposed indication while also characterizing potential toxicity profiles and target organs. Doses evaluated in the safety study should bracket the expected clinical dose level range. For example, the low dose is the minimally effective dose, the mid dose is the highest anticipated clinical administered dose, and the high dose is some multiple of the mid dose to provide some margin of safety.

Note that first-in-human doses should be selected using all available information, including clinical data. For example, CAR-T cell products often use clinical data from similar products to inform starting doses.

Takeaways

The nonclinical program to support safety of cell and gene therapy products should be tailored to each specific therapy. It is important to understand the biology of your therapeutic in order to design an adequate safety assessment. Talk early and often with regulatory agencies to gain agreement on the design and breadth of your proposed nonclinical safety studies; these interactions de-risk the program, provide you with the most up-to-date information on regulatory expectations for your therapeutic, and ensure patient safety.

Still not sure? Toxicologists within our Premier Consulting group can help you design and/or conduct appropriate nonclinical studies to support your cell or gene therapy product. Contact us today.

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