Streamlining orally inhaled product (OIP) development with EMA’s new guideline – the clinical perspective

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

Background

European Medicines Agency (EMA) published a new draft guideline on the requirements for demonstrating therapeutic equivalence (TE) between orally inhaled products (OIP) for asthma and chronic obstructive pulmonary disease (COPD), 20 years after the initial guideline came into effect.^1,2 After two earlier revisions in 2007 and 2009, this is a long-awaited major update of the original guidance. 

Several Q&A documents have been published by EMA’s Quality Working Party (QWP) and former Pharmacokinetic Working Party (PKWP) prior to this latest guideline release. The EMA has acknowledged that practices for development of OIPs have been formed through the Agency’s scientific advice and approvals, both of which were based on internal documentation that was not fully aligned with the guideline in effect. As a result, and because of the challenges in developing these complex products, the approval and adoption of generics for OIPs have also lagged behind.² 
The new guideline focuses on requirements for demonstrating TE between OIPs containing the same active moiety(ies), including single and combination products. The guideline still mainly applies to abridged applications (like original guideline) but has an additional consideration for when demonstration of TE is required. 

The new document complements the EMA’s Guideline on Pharmaceutical Quality of Inhalation and Nasal Products³ and the two should be read in conjunction. 

The new draft guideline brings several improvements 

The guideline continues to advise a stepwise approach to demonstrating TE of OIPs, starting with in vitro tests, followed by PK studies if needed, but generally eliminates the need for studies performed in patients. This is a huge improvement and simplification over the recommendations in the previous guidance.

Another shift in paradigm is that pharmacodynamic and clinical endpoint studies are generally no longer recommended as they are considered less sensitive compared to a PK study.

Also, studies in children/adolescents are less likely needed because extrapolation from adult data is allowed in many cases.  Again, these will simplify a typical study program of OIPs for drug developers.

EMA’s step-wise approach as a key strength

With the revised guideline EMA has stuck to its step-wise approach of demonstrating TE. The characterization of the in vitro properties of an OIP is the first step in the evaluation and demonstration of TE between the test and reference products. TE may be concluded entirely based on an in vitro comparison between the test and reference products, if all listed criteria in the guideline are met. Although the majority of products approved in Europe in the past still required a clinical study there are a few products were approval with an in-vitro assessment alone could be achieved, e.g. ipratropium bromide hydrofluoroalkane (HFA) for pressurized metered dose inhaler (pMDI). 

The main difference in the revised listed criteria is that a similar inhaled volume (±15%) through the device is no longer a requirement. 

For the Aerodynamic Particle Size Distribution (APSD) comparison, whereas the prior guideline provided vague requirements, the revised guideline lists a distinct set of criteria (e.g., APSD comparisons for flow-dependent inhalers should be done at three different flow rates [30, 60 and 90 L/min]). The previous acceptance criteria for comparisons were retained, however descriptive statistics are deemed sufficient in case of grouping of stages.

Unless all in vitro criteria are fulfilled, in vivo studies are needed to demonstrate TE.

Paradigm shift: therapeutic equivalence in healthy population PK studies (and not patients)

The most significant change in EMA recommendations for development of OIPs is that it is now acknowledged that that the PK/pulmonary disposition studies should typically be conducted in healthy adult volunteers because patient studies are considered less sensitive in detecting differences between test and reference products. Previously, the EMA required these studies to be performed in the intended patient population, or even as technically sophisticated imaging studies. 

The new guideline advises that only if pulmonary disposition studies are not sufficient to demonstrate TE, then a sponsor should demonstrate TE using appropriate pharmacodynamic and/or clinical studies. However, these studies are a burden for many pharmaceutical companies and practice has shown that a successful PK study often has been sufficient for approval.⁵ 

The EMA acknowledges that PK endpoints are considered valid surrogate markers to adequately predict similarity in the pattern and extent of deposition in the lungs and the systemic exposure; and, thereby, adequately predict equivalence in both efficacy and safety. The EMA reflects that it is generally not recommended for sponsors to aim at demonstrating TE using pharmacodynamic or clinical endpoints as these are deemed insensitive. EMA’s current position suggests product reformulation if PK data do not fulfill the acceptance criteria for PK endpoints. A clinical endpoint study in patients is considered the absolute exception, only if TE cannot be established kinetically.

With this paradigm change, not only has common practice in OIP development been acknowledged, but also unnecessary costs and the burden of patient studies have been eliminated in most cases. 

What is also important from a clinical practice standpoint is the use of charcoal blockade in the PK studies. To date, a study with and without charcoal blockade has been the standard in Europe for any OIP testing. Moving forward, this is only required for drugs with significant oral bioavailability (e.g., budesonide, formoterol, salmeterol). In case the absorption of the drug in the lung is very quick (e.g., median tmax ≤ 5 min) as for β2- agonists, a study without active charcoal blockade is also sufficient. Further, the use of partial area under the curve (AUC) is encouraged and for a drug with very quick lung absorption AUC0-30min can be used as a surrogate of efficacy (in a study without charcoal). From the OIP developer’s viewpoint, these are significant improvements from the previous guidance and reduce the need for further clinical studies.

Dry powder inhalers require special considerations

Dry powder inhalers (DPIs) are particularly influenced by the inspiratory effort of the patient. Resistance to airflow of the inhaler device is a major determinant for the inspiratory flow profile generated by the patient. Therefore, resistance to airflow is one of the design parameters for DPIs, that can be used to control the inspiratory flow profile and is one of the parameters to optimize particle deposition in the airways.⁶ 

In EMA’s new draft guidance, sponsors are asked to plot the percentage of disposition (FPD%) versus the flow rate (if devices have similar resistance to airflow) or versus the square root of the pressure drop (if devices have different resistance to airflow). Similarity can be concluded if the point estimate of FPD% of the test product is within ± 15% of the reference product for each tested flow rate or pressure drop. 

This is important because, for DPIs with similar flow rate dependency for the test and the reference product, a PK study in healthy volunteers is sufficient. If the flow rate dependency is not similar, TE cannot be concluded based on PK-data in healthy volunteers only (assuming a normal or high inspiratory flow rate) but additional PK data at a low inspiratory flow rate (around 30 L/min) is needed. Patients who have a low inspiratory flow rate due to the severity of their disease have problems inhaling an appropriate amount of drug, if the flow is compromised by the resistance of the device. However, such study does not necessarily need to be done in COPD patients but could be performed in healthy volunteers trained and monitored to inhale with low inspiratory effort or using an add-on device that increases the resistance to flow. This offers an opportunity for sponsors for a cost-effective development by relying on healthy volunteer data and its extrapolation to patients.

TE in children and adolescents can be established through extrapolation

The guidance now allows extrapolation of adult data to adolescents >12 years without further justification. In younger age groups extrapolation is also possible if similar dependency on flow rate has been established or exposures at lower inspiratory flow rates have been investigated. In case the device is not approved for children, data on usability needs to be provided. Nevertheless, this simplifies data generation and with the extrapolation concept, the necessity to study drugs in children has been significantly reduced. At the same time, it is still ensured that drugs for children <12 years of age remain in the focus of developers. 

As mentioned, usability (or human factors studies) for new devices may be required. The guidance also provides some details on the design of such studies for new devices. This information was not available in the previous guidance at all and created insecurity in the design of such studies. Drug developers may find it now helpful that expectations on sample size and the study population are clearly outlined, while clear acceptance criteria unfortunately are not further specified.

For children, if the device can be correctly handled and emptied and the in vitro criteria for TE have all been fulfilled, the age limit for the test product could be set at the same as the reference product without further data or justification.

In-vitro-in-vivo-correlation (IVIVC) - modelling on the rise

The new draft guideline allows for use of IVIVC in rare circumstances when it is difficult to find representative batches of the reference product and test product for APSD comparison. Modelling approaches were not discussed in the previous guidance. 

The goal of IVIVC is to build a model that can be used to predict in vivo outcomes from in vitro data. IVIVC is complex because it involves the consideration of numerous variables related to the formulation, inhaler, environment, and patient.⁴ Often no IVIVC is available to guide the developers. Another major challenge – also discussed in the draft guidance – is that batch-to-batch variability can be significant, both in vitro (APSD) and in vivo (PK) due to aging of the products. 

Although the draft guidance does not give details on the IVIVC modelling itself, it allows the normalization of the PK data to results expected for a “representative batch”, in scenarios when it is difficult to find representative batches. However, such an approach may be acceptable only if an IVIVC has been established before and pre-defined in the protocol. We are seeing an increase in modelling use, as the value and its application has increased over the years. It can address differences in batches that are otherwise difficult to overcome. 

Altogether, EMA has made a big leap forward and a typical investigational program becomes less burdensome which has the potential to foster the development of OIPs as complex generics in Europe.

As a leading global phase I-IV clinical research organization, Parexel leverage the breadth of our clinical, regulatory and therapeutic expertise to optimize your clinical development programs and to help you navigate the regulatory agency requirements. Parexel’s Regulatory Consulting group interprets evolving regulatory requirements, prepares robust submissions, and effectively manages interactions with regulatory agencies, ultimately helping to bring innovative therapies to patients more efficiently and effectively. Please contact us  to further discuss how we can support your development of OIP products.
 

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References

1. EMA/CHMP/101453/2024. Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and chronic obstructive pulmonary disease (COPD)
2. CPMP/EWP/4151/00 Rev. 1. Guideline on the requirements for clinical documentation for Orally Inhaled Products including the requirements for demonstration of therapeutic equivalence between two inhaled products for use in treatment of asthma and chronic obstructive pulmonary disease (COPD) in adults and for use in the treatment of asthma in children and adults.
3. Newman B, Witzmann K. Addressing the Regulatory and Scientific Challenges with Generic Orally Inhaled Drug Products. Pharmaceut Med. 2020 Apr;34(2):93-102. doi: 10.1007/s40290-020-00327-y.
4. EMEA/CHMP/QWP/49313/2005. Guideline on the pharmaceutical quality of inhalation and nasal products.
5. Chow, M. Y. T., Tai, W., Chang, R. Y. K., Chan, H. K., & Kwok, P. C. L. In vitro-in vivo correlation of cascade impactor data for orally inhaled pharmaceutical aerosols. Advanced Drug Delivery Reviews 2021, 177, 113952.
6. Usmani OS, Molimard M, Gaur V, Gogtay J, Singh GJP, Malhotra G, Derom E. Scientific Rationale for Determining the Bioequivalence of Inhaled Drugs. Clin Pharmacokinet. 2017 Oct;56(10):1139-1154. 
7. de Koning JP, van der Mark TW, Coenegracht PM, Tromp TF, Frijlink HW. Effect of an external resistance to airflow on the inspiratory flow curve. Int J Pharm. 2002 Mar 2;234(1-2):257-66. doi: 10.1016/s0378-5173(01)00969-3. PMID: 11839456.

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