There are several distinctive features that must be considered in the ATMP development:

  1. ATMPs are mainly for the unmet medical needs = severe, rare, or chronic diseases with no adequate conventional treatments.
  2. Risk-based approach = Dominant strategy of the ATMPs development.
  3. ATMP = strong scientific data + consistent/robust/aseptic manufacturing process.
  4. Early start with the potency assays development (mode of action/the intended effect).
  5. Quality = starting materials, raw materials, supply chain, etc.
  6. Preclinical safety assessment (immunogenicity, biocompatibility, viral or bacterial contamination, ectopic tissue formation, tumorigenicity, mutagenesis, tropism and tissue distribution, stability, biodistribution, shedding, etc.).
  7. Difficulties with the reproducibility and high variability (donors, patients, batches, etc.).
  8. Bidirectional Traceability system.
  9. Designing In Process Control Tests (comparability tests) and Product Release Tests (identity, concentration, viability, recovery, impurities, etc.), including method/tool/equipment validations behind the tests.
  10. Formulation, packaging, storage/cryopreservation, and transportation conditions do have a strong impact on the intended effect.

Have you experienced additional difficulties in your ATMP development? We would love to learn more about your development program and explore how we can impact your work.

Let us facilitate your ATMP advancement in the minimum of time and with the most efficient use of resources, while ensuring the high quality. It would be great to establish a cooperation between Venn Life Sciences and your company.

Discover how we can support and accelerate the ATMP development:

Blog written by Ion Tcacencu

Ion Tcacencu (MD, PhD) is an ATMP expert with over 17 years of experience as scientist within regenerative medicine and immunology, being responsible for projects developing new ATMPs.

Appropriate scale-up/down is key for further larger production. Important is to focus to the right parameters that can help us to set the design for all experiments at lab scale.
The common approach within the up-stream processing (USP) part in biologics is to increase the scale 10 times. It means from e.g. 25L lab scale to max. 250L pilot scale and later on from pilot scale to max 2500L production scale. Key parameters are vessel geometry, agitation, aeration, back-pressure and feeding profiles (in case of fed-batch fermentation). Next diagram shows typical construction of a common fermenter with key parameters:

Geometric similarity of fermenter geometry is a pre-requisite for applying established scale-up relationship. It´s expressed as follows: DT2/DT1 = (VT2/VT1)1/3, where DTi is fermenter diameter and VTi total fermenter volume. Geometric similarity also assumes reasonably constant impeller geometry such as impeller diameter (DI) and number of impellers (N). Based on target total a/o working volumes obtained from geometric similarity, the desired working volume in the fermenter may be altered during experimentation. The ratio of the impeller to fermenter diameter (DI/DT) in standard fermenters is between 0.3 to 0.45. Fermenters with a standard geometry are beneficial within scale-up correlations assuming constant geometry. Common pilot scale-up fermenters have HT/DT ratios of 3:1, but they can also decrease to 1:1.

The first approach within agitation is to check the design of impellers, number of impellers, diameter and location. Common impellers used within microbial fermentations are Rushton turbines or Hollow-blade (U-shape), but could also be Hydrofoil, Maxflo, etc. Stirrer tip speed (STS) is the simplest approach normally used in case of same design of impellers between two scales. It is formulated as STS = πNIDI, where π is a constant, NI and DI are the impeller speed (s-1) and impeller diameter (m) in fermenter respectively. Typical STS ranges from 3.8 to 7.6 m/s.

More complex approach within agitation is Constant (gassed) power input per liquid volume (PG/VL) which characterizes energy generated by impeller to liquid volume used in the fermenter. It is normally used in a case of scale-up for various design of impellers between two scales. PG/VL is expressed as PG/VL = P0/VL*0.5 = ((NPNI3DI5ρ)/VL)*0.5, where NP is the power number, which means proportionality factor based on impeller design (NP for Rushton is 5 and for Hollow-blade  is 1.5). NI and DI are the impeller speed (s-1) and impeller diameter (m), ρ is specific broth density (kg/m3) and VL is volume of fermentation broth (L). General values of PG/VL in large scale (fermenter with a total volume more than 1500L) are between 1 to 3 W/L. It´s difficult to have high power per unit volume at the large scale due to practical limitation of the motor size.

Additional scale-up parameters are focused to oxygen transfer. They are Oxygen Uptake Rate (OUR) and Mass transfer coefficient (KLa). Scale-up based on OUR assumes that the OUR is equal to Oxygen transfer rate (OTR). This equation is expressed as OTR = KLa(csat – cL) = OUR = μX/YX/O2 , where csat is the broth dissolved oxygen (DO) at saturation, cL is the measured broth DO concentration, μ is the specific growth rate, X is the measured cell density and YX/O2 is the cell yield calculated per amount of consumed oxygen. There are several correlations for the determination of KLa using Gassed power per liquid volume (PG/VL) described previously and Superficial gas velocity VS, where the formula looks is KLa = f2(PG/VL)aVSb , where f2 is a proportionality constant. In general, the “a” value within this equation decreases with increasing working volume. The “a” value is  0.95, 0.67 and 0.5 for fermenters from lab scale (e.g. 10L scale), pilot scale (300L) and production scale (more than 20,000L) respectively. Same holds for the “b” value: 0.67 for lab and pilot scale and 0.50 for production scale. The formula for Superficial gas velocity (VS) is VS = φG/(π/4)*DI2), where φG is Gass flow rate (m3/s)  and DI is impeller diameter (m). Finally Gass flow rate can be calculated using φG = (Q * (tact/t0)*(Patm/Pabsolute))/3600, where Q is airflow rate (Nm3/s), tact and t0 are actual temperature and temperature of absolute ZERO in Kelvin and finally Patm and Pabsolute are the pressures. Production fermenters up to 100,000L scale have KLa value between 400 to 800 h-1. Scale-up based on KLa is complicated approach by the fact that it is process specific and it changes over the fermentation, making it difficult to reliably quantify. Alternatively, measurement of broth DO concentration (CL) can be used as an adequate scale-up parameter. The minimum acceptance value of CL is well known from lab scale experiments. Cascade control of DO by agitation, aeration and back-pressure can be effective in maintaining of DO above critical value.

The Table 1 shows an example of most important parameters within scale-down model from 300L pilot fermenter to 75L lab fermenter. Appropriate set of all required parameters in small scale can be predictive for consecutive production in large scale. Finally, all set process parameters need to be confirmed in larger scale via pilot or ENG/Validation batches within further cGMP production.

CMC experts from Venn Life Sciences have strong expertise within theoretical and practical application of these models. Do you need more insight or support with your up-scaling process? Do not hesitate to contact us via our website:

Table 1. Practical application of scale-down model from pilot fermenter (300L) to laboratory fermenter (50L).

300L pilot fermenterFermenter parameters used for Scale down75L lab. fermenter
3.32Ratio HT/DT3:1
200LWorking volume Vmax50L
Rushton, 3 timesImpeller type and No.Rushton, 3 times
0.23Impeller diameter DI0.12
4 kWEngine power PE1.1 kW
22 kW/m3Engine input per working volume PE/VL = PE/(Vmax/1000)20 kW/m3
420 rpm = 7 rpsAgitation Nmax800 rpm = 13.33 rps
5.06Stirrer tip speed STSmax = πNmaxDI5.03
16.8 Nm3/h = 280 L/minAirflow rate Qmax6 Nm3/h = 100 L/min
1.40 vvm (1/min)Volumetric airflow rate per volume Qmax/Vmax2 vvm (1/min) Scale down recalculation to 1.4 vvm corresponds to airflow 70 L/min
5.15 W/L (for Nmax)Constant (gassed) power input per liquid volume P0/VL*0.5 = ((NPNI3DI5ρ)/VL)*0.55.50 W/L (for Nmax) Scale-down recalculation to 5.15 W/L corresponds to agitation 782 rpm

Note: For successful scale down model is necessary to set appropriate parameters in lab. scale such as agitation, aeration and back-pressure, that mimic parameters in pilot scale.

Date: 24.10.2022

Author: Juraj Boylo

CMC evolution during gene therapy development

Gene therapy offers significant potential to treat diseases with high unmet medical need. However, the unique nature of these therapies poses challenges in product development, namely: safety concerns, efficacy issues, or obstacles related to Chemistry, Manufacturing and Controls (CMC). CMC is an integral aspect of gene therapy development. Done right, CMC development of complex manufacturing processes and analytical testing panels can accelerate clinical development and bring these important medicines to patients faster. For gene therapy products, CMC development often needs to be done in a highly compressed timeline, and there are important CMC challenges that need to be addressed to bring these products into the clinic and beyond, amongst which:

  • Manufacturing process should be GMP compliant
  • Variability and quality of starting materials
  • Vector characterization
  • Cell bank qualification
  • Setting proper drug substance and drug product specifications
  • Selecting a potency assay, which should eventually link to both the drug’s clinical efficacy and its mechanism of action
  • Viral clearance
  • Microbial safety
  • Stability / shelf life of the product
  • Changes in the production process, raising comparability issues 
  • Upscaling of the production process
  • Changing site of production
  • Environmental assessment

Gene therapy products are similar to other biological products in many ways. CMC hurdles in development of biologicals/ biotechnological products are common to our Venn experts; they have key experience in providing support in the development of a wide range of complex biological products. Their broad expertise allows them to have a holistic view on the CMC development of gene therapy products, and to provide out-of-the-box solutions. In example, their experience with human adenovirus-based vaccines allows to translate this expertise to adeno associated virus (AAV)- based gene therapies. The Venn CMC team is well aware of the requirements for early (Phase I) and later (Phase II and III) phases of development and can support you in CMC challenges you are facing in your gene therapy development. The Venn CMC team can help the client to find the optimal solutions to drive your product in development to clinical success.

One of the first steps is creating a solid roadmap for your product, a drug development plan, which outlines your drug development strategy and contains a carefully planned set of steps and action plans, progressing from non-clinical to the first-in-human Phase I to Phase II “proof of concept” and pivotal Phase III trials for registration. Our Venn experts can guide through your journey and can built a comprehensive drug development strategy for your product.

The next step is to support you in early and timely discussions with regulatory agencies on your development plan. Priority for agencies is to keep patients safe. Regulators want to see that a sponsor has control over its products and processes in development. Sponsors should therefore take advantage of, e.g., Innovation Task Force meetings and scientific advice meetings with the EMA or EU national authorities, and/ or INTERACT and Pre IND meetings with the US FDA, to seek advice and alignment with the agencies on CMC challenges you are facing, and the solutions and path forward you are proposing. The Venn regulatory team can plan and manage your health authority interactions. Our consultants are experienced in generating scientific advice/ Pre-IND briefing packages and liaising with US and EU regulatory agencies. They can also act as sponsor representative during EU scientific advice procedures.

Once you have tackled the CMC hurdles and you have buy-in from the agencies on your drug development plan, you can start planning the first-in-human Phase I trial for which you need to produce GMP-compliant investigational product, and for which you need to submit a clinical trial application. The Investigational Medicinal Product Dossier (IMPD) in the EU, or Investigational New Drug (IND) dossier in the US, is one of several pieces of the investigational product related data required for this application. The IMPD/ IND includes information related to the quality, manufacture, and control of the investigational product (including placebo). Guidance on the structure and CMC data requirements for investigational gene therapy products exists for EU and US applications. The EU and US guidelines for investigational
gene therapies have been built on the existing IMPD/ IND guidelines for biologicals/ biotechnological products, and the Venn CMC team is well equipped to support you in authoring the IMPD/ IND.

In addition to the clinical trial application, gene therapy products classified as genetically modified organisms will be subject to a GMO application to the applicable biosafety agencies in the EU to permit the release of the product into the environment (so-called biosafety review). Pending on the modalities of the use, the product can be considered to be contained use or deliberate release, each coming with a different set of requirements. The expectations for environmental risk assessments and GMO applications are regulated on a national level and the requirements and classification can therefore vary significantly between member states in the EU, resulting in a maze of requirements that are difficult to navigate. The Venn regulatory team can guide you in this process and can help you with the procedural aspects of the GMO application and clinical trial application.

In conclusion, there are important CMC challenges that need to be addressed to bring a gene therapy product into the clinic and beyond, but many aspects of gene therapy development are similar to other biological products. With guidance and expertise of our Venn experts in the biological/ biotechnological field, your chances of a successful outcome of your gene therapy development will be increased.

Setting the scene

Over the past century, vaccines have made a large impact on public health, as recently demonstrated by the treatment of the worldwide Covid-pandemic. Since, in general, vaccines are administered to healthy individuals, including infants and children, it is important to demonstrate the safety of vaccines with proper in vitro testing and in vivo animal testing prior to starting clinical studies with the vaccine candidate. Therefore, over the past decade, there has been an increased focus on nonclinical safety assessment of vaccines, including testing for potential toxicity.

Non-clinical guidelines for vaccines

Over time, the extent of nonclinical safety testing has been greatly increased and current regulatory guidelines (see inset) require a comprehensive package of safety studies to be performed. These guidelines are aligned with overall principles of toxicological evaluation (i.e., detection of potential for systemic and local toxicity) but allow for appropriate flexibility in study designs according to the type of the vaccine candidate, the specific disease for which the vaccine will be used, the human population to be treated and the dosing regimen to be applied in the clinical use (see inset).

Most important general guidelines describing nonclinical studies supporting clinical trials for vaccines are:

In addition, there are many guidelines, focusing on type of vaccine (e.g. live attenuated, inactivated, toxoid, recombinant protein, conjugated, RNA, DNA vaccines), specific diseases (e.g Covid, Influenza, Hepatitis, Yellow Fever, Rabies, Tuberculosis) and human population to be treated (e.g.adults, pediatric, juveniles)

Strategy for nonclinical safety/toxicity testing

Prior to starting clinical studies with vaccines, adequate information about the pharmacology and toxicological effects of the vaccines should be available. The program of safety studies to be performed varies depending on the type of vaccine, disease to be treated and intended use in humans (e.g., number of injections). It is important to have an optimized strategy and planning of the proper non-clinical studies to best and quickest transition into clinical studies. Nonclinical testing of vaccines is different from testing of small molecules and the appropriate (combination of) studies has to be deducted for each specific vaccine candidate based on applicable guidelines and experience.

Regulatory toxicology studies for testing the safety of vaccines are performed in vitro and in animal studies and need to be performed in compliance with Good Laboratory Practice (GLP). Venn experts can help you in selecting CRO’s, in monitoring the progress of your studies, reviewing reports and in drafting regulatory documentation.

Next step - clinical (challenge) studies

A clinical development approach that has become more commonplace in recent years, is to test different dosing regimens in a Human Challenge Study. In example, different adjuvants and dosing approaches (with or without booster) are tested in these challenge trials, to obtain the best possible dosing regimen for phase 2 / 3 field trials. In the design of your nonclinical safety/toxicity testing program, you also have to take into account these options to allow you to take the most out of the challenge trials and optimalise your development program.

Venn experts can help you to select the appropriate studies and define a Drug Development Plan for your vaccine candidate.

Why Venn’s Non-Clinical team

The IND filing and first clinical studies for your lead vaccine can be a lengthy and costly process. Developing the right strategy and study designs is the first step in the direction toward an optimized nonclinical program. The combination of specific scientific non-clinical expertise combined with detailed knowledge of regulatory requirements for vaccine development, commitment to your projects and the constant pursuit of quality excellence make Venn a reliable source for Non-Clinical Consultancy Service for your vaccine projects.

Each journey begins at a starting point, and we believe that few journeys are as exciting as developing a drug. In order to succeed and reach your destination, you need a solid roadmap, the drug development plan (DDP), this is the outline of your drug development strategy. 

A comprehensive drug development strategy outlines each step for advancing a new compound from the lab through each stage of development, ultimately arriving at the envisioned marketed drug product. 

This requires a multi-disciplinary project team of experienced experts in strategic planning, which outlines the chemistry, manufacturing, and controls (CMC) and formulation activities, key non-clinical studies, and Phase I-III clinical trials, regulatory submissions, and health authority interactions, market launch activities, and life-cycle management. A drug development strategy is a dynamic process that moves forward in defined stages. A carefully planned set of steps and action plans, progressing from non-clinical to the first-in-human Phase I to Phase II “proof of concept” and pivotal Phase III trials for registration.

The drug development process can be complex and involves various strategic steps that can reduce timelines and costs

A proper development strategy should answer the following:

  1. What is the intended target population and indication?
  2. What are the desired product attributes: indication or usage & dosage, administration & pharmacology, adverse reactions & toxicology, clinical data, clinical safety, and efficacy. 
  3. Identifying the most feasible country for clinical trials. global data acceptance, developmental infrastructure, clinical developmental costs.
  4. Identifying the most efficient and effective ways for clinical developments
  5. What are the potential markets and what are your marketing strategies?

Identifying these steps early is an essential part of a successful development. Our Venn experts can guide through your journey.

At Venn Life Sciences, our team of experienced consultants have the expertise to help with the various steps in drug development to ensure that you receive the support and direction required to formalise your drug development. We have integrated drug development partners offering a unique combination of drug development consultancy, clinical trial design and execution.

Learn more about our drug development services here.

The first‐in‐human (FIH) clinical trial is an important milestone for each development program. For small (bio)pharma companies the FIH trial requires a significant investment, and every sponsor wants to make sure that all is well set for starting the trial.  It is indisputable that successful execution of the FIH trials does require sponsors to coordinate the task with thorough consideration and planning across many disciplines. Especially, selection of the starting dose requires a cross‐functional collaboration, where preclinical knowledge needs to be transformed into clinical applications. This step could become a large hurdle which could even retard the progress of the program, if planned and strategic alignments are not reached within the project team as well as adequate actions are not taken well in advance of the FIH trial.

Over the past years, Venn Life Sciences as a consultant company, has been exposed to a significant number of FIH trials both in healthy volunteers as well as oncology patients. In this blog, we like to highlight several considerations, based on these experiences, that will need to be addressed for defining the starting dose and beyond in the FIH trial. 


The EMA’s FIH guideline says, “Depending on the level of uncertainty regarding the human relevance of findings observed in nonclinical studies and the knowledge of the intended target, the starting dose should either be related to the MABEL (Minimum Anticipated Biological Effect Level), PAD (Pharmacologically Active Dose) or NOAEL (No Observed Adverse Effect Level).” Thus, the choice of MABEL- or NOAEL-based starting dose selection must be driven by overall assessments of available data and risk-based considerations. Typical factors for the assessments include but are not limited to:

It is highly recommended to make a rationalized choice of the MABEL- or NOAEL-based approach (e.g. using decision tree) with adequate documentation in investigator’s brochure, as this is a critical point of review by the competent authority/ethics committee.

Do you have sufficient/adequate data set for MABEL calculations?

To employ the MABEL-based starting dose establishment approach, it is essential that relevant data sets have been generated by the sponsor. Unlike toxicology (NOAEL)-based approach for FIH dose selection, which is rather straightforward, the type of data required for MABEL calculation can differ case by case (e.g. in vitro and/or in vivo data and in recent years increasingly involve modelling and simulation). Since generation of relevant data may take several months, any absence of relevant data for the MABEL calculation could cause a significant delay in the program. Therefore, it is pivotal that the project team plans this exercise way in advance of the FIH preparations.

How to define “minimum” effect?

One of the most frequently asked questions in terms of MABEL calculation is what degree of a biological response is considered “minimum”. Unfortunately, there is no standard answer for the question, and this is nowhere well-defined in the guidelines, as there are multiple unique factors that may need to be considered for each investigational product. For example, since receptor occupancy required for efficacy are expected to be different between antagonists and agonists even if the same receptor is targeted, different considerations are likely required for defining the MABELs for such cases. Ultimately, the sponsor is responsible to scientifically justify underlying rationale for defining the MABEL.

Starting dose calculation

While mechanistic state-of-the-art modelling (e.g. PK/PD and PBPK) is increasingly used in the calculation of the starting dose based on NOAEL, PAD and MABEL, it should be emphasized that the EMA guideline also refers to the application of allometric factors. Unless the drug product is associated with significant safety risk in human based on preclinical finding and/or a certain drug class (e.g. immune stimulator) and thus requires more sophisticated mathematical approach, empirical allometric scaling approach in combination with a simulation of exposure-pharmacological response relationship in human might also be sufficient for the starting dose selection for the FIH trial in healthy volunteers. Irrespective of approaches chosen, careful deliberation on the planning of the starting dose assessment is required, as unnecessary assessments during this process may also cause a delay in the program and a needless financial burden.

Applying safety factors

After the calculation of the MABEL, PAD, or NOAEL, additional safety factors are applied to account for several potential risks, such as the relevance of animal models, any uncertainties in the estimation of the MABEL, PAD, or NOAEL, or other unique safety or pharmacodynamic characteristics of the investigational product. Inadequate assessment of the safety factors may result in unnecessary risk for volunteers, or unnecessarily low doses in the first cohorts and as such additional dose escalation cohorts may be needed.

Be clever in trial design/protocol

Despite of all exceptional efforts and fancy mathematical MABEL calculations, pharmacokinetic properties might behave differently in human in the FIH trial, especially at the low starting dose, where PK tends to be non-linear. The clinical trial protocol, therefore, should clearly define the dose escalation rules to allow for the dose escalation to proceed in a scientifically, ethically as well as financially acceptable way. For example, the clinical protocol should include adequate language to allow for more aggressive dose increments, in case the observed exposure at the starting dose is significantly lower than predicted. Otherwise, volunteers will continue to be administered at dose levels even lower than the MABEL, which may result in the need of additional cohorts, or in the case of patients, treatment at an unnecessarily low and ineffective dose. We highly recommend authoring an adaptive FIH protocol, which will allow adjustments in the dosing schedule, circumventing delays in the trial execution.

Concluding remarks:

Tom Habraken (MSc) is Consultant Clinical Pharmacokinetics at Venn Life Sciences. He has over 6 years of experience in pharma/consultancy industry. He is an expert in Clinical Pharmacokinetics and has been involved in FIH trials in healthy volunteers as well as oncology patients. Tom is also an organizer and trainer of Venn’s Pharmacokinetics Course (LINK).

Marieke van den Dobbelsteen (PhD) is Senior Consultant Clinical Development as well as acting as Group Leader in Clinical Trial Management and Medical Writing Team at Venn Life Sciences. She has over 25 years of experience in pharma/consultancy industry. She is an expert in early drug development (early-clinical) and has ample experiences in managing as well as providing consulting for early clinical development including FIH trials.

Theo Reijmers (PhD) is Consultant Pharmacometrics at Venn Life Sciences. He has over 6 years of experience in pharma/consultancy industry (+ >10 years in academia). Theo is a pharmacometrician and has ample experience in PK/PD translational modelling in early-stage drug development (e.g. human dose prediction for first-in-human studies). He also has experiences with submitting modelling related output to FDA and EMA.

Katsuhiro Mihara (PhD) is Senior Consultant Clinical Development as well as acting as Head of Clinical Development Department at Venn Life Sciences. He has over 25 years of experience in pharma/consultancy industry. Katsu has a broad knowledge on early clinical development, clinical pharmacology as well as translational science and has been involved in numerous numbers of early-stage clinical projects as well as scientific due diligence projects for investors/pharma.

If you are interested to learn more about how to define a safe starting dose for your FIH trial, please contact Venn life Sciences at We would welcome the opportunity to discuss efficient set up of your FIH trial and other related aspects.

Did you ever ask yourself one of the following questions?:

Statistics play a fundamental role at each step of a clinical trial (trial design, protocol development, the statistical analysis planification and execution, interpretation of the results). With the evolution of statistical science (e.g., progresses in the understanding of mechanisms generating missing data and methods to handle missing data) and the development of new clinical trial methodology concepts (e.g. adaptive designs, master protocols…) new challenges have emerged.

The recent adoption of the ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials and methods in 2020 reshaped the approach to study design and protocol development. An estimand is a precise description of the treatment effect to be estimated. The estimands have to be defined upfront, before considering the methods for answering the question (the statistical analysis itself). Clear study objectives and the scientific questions of interest have to be precisely described. Estimands consistent with the question of interest are then defined. Only after the estimands have been defined can the trial be adequately designed, ensuring all the data necessary to the estimands are collected. Finally, the statistical analysis methods can be chosen.

As a non-statistician clinical trial professional from the pharmaceutical industry, biotech industry or health research, you may feel uncomfortable with some statistical concepts or methods and in your interactions with statisticians.

At Venn Life Sciences Biometry Services, our expert methodology and biometry consultants provide training to fulfill this gap.

Several topics can be covered, and a training program specifically tailored to your own needs can be prepared:

Statistical principles

Descriptive statistics

Inferential Statistics (Hypothesis tests)

Confidence intervals

Frequentist vs Bayesian inference

Type of variables

Measures of treatment effect

Choice of statistical test

Statistical modeling Sample-Size and Power


Design (parallel groups, crossover, factorial…)

Interventional/ non interventional studies

Bias reducing techniques (Randomisation Blinding)

Objectives, Endpoints


Dose finding

Interim analyses

Adaptive designs

Master protocols (Basket; Umbrella, Platform- trials)

Diagnostic tests

Metanalysis Data Monitoring Committees

Planification of Analysis

Analysis populations


Superiority/Non inferiority, Equivalence

Handling of Missing data

Subgroup analyses


Interpretation of results


Critical appraisal

Example of recent training activities

  • A half-day introduction to Adaptive Designs for a Clinical Development team
  • A half day training on Interim Analyses for a Biostatistics team
  • A one-day training on the ICH E9 (R1) addendum and the estimand framework for the Biostatistics and Medical Writing teams
  • A three-day training on Statistics for Non-statisticians for the Clinical Development and Medical Affairs teams
  • A half day training on Non-Inferiority and Equivalence studies for a Biostatistics team
  • A short introduction on the Design for Phase I Ascending Dose studies for a Clinical Development team

The Food and Drug Administration (FDA) is an agency within the U.S. Department of Health and Human Services. It is the US Agency responsible for the regulation of drugs and biologics, including, vaccines for humans, blood and blood products and cellular and gene therapy products.

As the United States remains the largest pharmaceutical market in the world, any drug development program will require a close interaction with the FDA to ensure your development rationale is sound and that the design of your studies is fit-for-purpose.

Although a first contact with the FDA might sometimes feel intimidating, an early interaction will prove very valuable. Your first interaction with the FDA will likely be a pre-IND meeting. Sensu-stricto a pre-IND meeting is not required, it is however highly recommended to engage with the FDA in a pre-IND meeting for the following reasons:
Early Feedback from the FDA - The most valuable benefits of the pre-IND meeting are to receive early feedback directly from the FDA on your development program and to gain an understanding as to what the FDA’s expectations are for your drug.

Fine-Tuning of your Development Strategy – Taking the feedback in the FDA into account, offers you the opportunity to fine-tune your program development strategy, potentially saving time and money.
Relationship Building – The pre-IND meeting is also the opportunity to start building a working relationship with the FDA and individuals within the Agency that will be your contact persons.

In preparation of your pre-IND meeting, you will need to prepare a briefing package. In this briefing package you will provide background information on your compound and prepare the list of questions. When preparing these questions, there a few things you need to keep in mind:

• FDA meetings are most effective when they are focused on specific scientific or regulatory issues, such as clinical trial design, pharmacology studies, toxicology studies, acceptability of novel formulations, dosing limitations, data requirements for an IND application, etc.

• Speculative and open-ended questions are difficult to address; meetings are typically most productive when questions are focused and specific. Questions for the FDA should be posed in such a way that the agency can either agree or disagree with the question.

As the briefing package forms the basis of a successful meeting, it is important that it is well worked out. Taking advantage of the valuable input that can be gained from pre-IND meetings is essential for the further development of the drug and may reduce the drug’s time to market and ensure that the proposed studies are designed to provide useful information. Sponsors who are forthcoming with potential issues of concern during the drug development process will benefit from input provided by the regulatory agency.

Bruno Speder is currently VP, Regulatory Affairs & Consultancy Services at hVIVO & Venn Life Sciences, part of Open Orphan. He advises clients on the regulatory strategy of their vaccine development and supports them in their interactions with the Food and Drug Administration, European Medicines Agency and the national regulators in Europe. He holds a degree in Bioengineering from the University of Ghent, Belgium.

If you are interested to learn more about how our Regulatory Affairs department can support your development activities, please contact Venn life Sciences at