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 OPIs 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 Products ³ 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 t max ≤ 5 min) as for β 2 - 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 AUC 0-30min 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.

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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