The US and EU Regulatory Landscapes for Locally Acting Generic/Hybrid Inhalation Products Intended for Treatment of Asthma and COPD

Abstract

This is a review of the current regulatory requirements associated with development and submission of abridged dossiers for locally acting inhalation drugs intended for the treatment of asthma and chronic obstructive pulmonary disease. The current EU law does not provide for submission of such products as generics due to the definition of bioequivalence and bioavailability; instead they must be submitted as hybrids. A guideline from 2009 is available that suggests a stepwise approach toward approval. An applicant should first consider the degree of in vitro match with the reference product; provided that the match is extensive, approval may be granted. If the in vitro match cannot be proven, the next step is comparison of lung deposition and systemic exposure. If this match is proven, approval may be granted; otherwise, the final step is pharmacodynamic evaluation. In the United States, submission as a generic is possible, but only a single specific guidance document from 1989 is in force. It describes in vitro requirements for comparison of albuterol and metaproterenol pressurized metered dose inhalers. Applicants are encouraged to seek dialogue with regulators prior to and during development. Although parallel scientific advice procedures have been established between the US Food and Drug Administration and the European Medicines Agency, the two authorities give independent and individual advice.

Introduction

This is a review of the regulatory requirements for orally inhaled drug products (OIPs) that, in whole or in part, are copies of a reference inhaled drug product and submitted for approval in the United States or Europe. A presentation at the 18^th Congress of the International Society for Aerosols in Medicine served as precursor for this review. It focuses on drug products containing locally acting active pharmaceutical ingredients (APIs) intended for treatment of chronic obstructive pulmonary disease (COPD) and asthma. Antibiotics (e.g., for cystic fibrosis) or drugs for which the API needs to reach the bloodstream before it is distributed to the site of action (e.g., inhaled insulin) are outside the scope of this work. The review furthermore focuses exclusively on the formal requirements associated with development and submission of products for which therapeutic equivalence (as defined in the EU; see below) or bioequivalence (as defined in the United States; see below) is intended to be shown. Such formulations will be subject to a range of requirements (stability, leachables and extractables, etc.) that are common to—and the same for—both innovator and generic/hybrid drug products, and these requirements are therefore outside the scope of this review. Finally, the review makes no deep attempt at drawing conjecture about the requirements in areas where enforced guidance does not exist, and thus does not go into depth about requirements that are specified in draft guidance documents, as these may, in part or entirety, not be enforced.

Submission bases, routes, and the essential definitions

Europe

The laws regulating the approval of medicines in Europe are laid down in the European Community Directives. The overarching directive is “Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use,”⁽¹⁾ which in the following is referred to as 2001/83. Articles 10.1 and 10.2 of 2001/83 define the submission basis for a generic that is a product “(…) whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.”

Article 10.3 states further:

“In cases where the medicinal product does not fall within the definition of a generic medicinal product as provided in paragraph 2 (b) or where the bioequivalence cannot be demonstrated through bioavailability studies or in case of changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, vis-à-vis the reference medicinal product, the results of the appropriate pre-clinical tests or clinical trials shall be provided.”

It is noted that directive 2001/83 is void of certain definitions. Bioequivalence is defined in the guideline “Investigation of Bioequivalence” (a guideline that is not specific to inhalation products): “Two medicinal products containing the same active substance are considered bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and their bioavailabilities (rate and extent) after administration in the same molar dose lie within acceptable predefined limits.” In practice, this implies that bioequivalence is tightly linked to pharmacokinetics (or in rare cases urine sampling), but not pharmacodynamics. As the European guideline (detailed later) allows approval for OIPs on the basis of in vitro studies, pharmacokinetics studies, or pharmacodynamics studies, the submission basis is not article 10.1/10.2, but 10.3. This has an important implication in that generic OIPs in Europe formally do not or should not exist. Furthermore, as the European definition of bioequivalence is linked to pharmacokinetics and because methods other than pharmacokinetics might be necessary to show the similarity to a reference product (see the “Studies” section), the goal of the investigation is termed “therapeutic equivalence,” which does not have a legal definition.

United States

In the United States, the definition of bioequivalence differs from that used in Europe. The Food, Drug and Cosmetic Act defines it as⁽²⁾:

“The term ‘bioavailability’ means the rate and extent to which the active ingredient or therapeutic ingredient is absorbed from a drug and becomes available at the site of drug action (…) For a drug that is not intended to be absorbed into the bloodstream, the Secretary may assess bioavailability by scientifically valid measurements intended to reflect the rate and extent to which the active ingredient or therapeutic ingredient becomes available at the site of drug action (…) For a drug that is not intended to be absorbed into the bloodstream, the Secretary may establish alternative, scientifically valid methods to show bioequivalence if the alternative methods are expected to detect a significant difference between the drug and the listed drug in safety and therapeutic effect.”

Under these definitions, bioequivalence can be shown using techniques other than comparative pharmacokinetics, such as pharmacodynamics if sensitivity is proven.

The legal submission basis for a generic filing is given by clause 505(j)⁽²⁾:

“Any person may file with the Secretary an abbreviated application for the approval of a new drug (…) An abbreviated application for a new drug shall contain (…) (i) information to show that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the new drug have been previously approved for a drug listed under paragraph (7) (hereinafter in this subsection referred to as a “listed drug”) (…) [as well as] information to show that the new drug is bioequivalent to the listed drug.”

Thus, orally inhaled products can, at least in theory and in contrast to Europe, be generic. There is, to the knowledge of the author (as of March 2012), no approved product in the United States that has been submitted under 505(j); obstacles include, without being limited to, lack of guidelines, lack of validated endpoints for equivalence demonstration, lack of statistical framework for the equivalence exercise, variability of reference products, and not least lack of technology that consistently guarantees a test product to consistently match the reference drug.

A second submission basis exists in the United States, where an applicant can refer to studies of an originator product (or more if they exist). This is the 505(b)(2) application⁽²⁾; it distinguishes itself from 505(j) in that the proposed product need not be bioequivalent to any other product. It might be equivalent in some sense, but as a new drug it needs to introduce some novelty.

European submission routes

A hybrid submission in Europe can follow different routes, which I will loosely define as the method the applicant chooses to get to the market for a product with a given submission basis. As the EU laws preserve national sovereignty, approvals may be purely national or they might, as directive 2001/83 provides for,⁽¹⁾ be approved using mutual recognition procedures (MRPs) or decentralized procedures (DCPs)⁽³⁾:

• A purely national approval follows the rules of each individual country (including timelines for assessment and costs of submission).

• An MRP can be initiated after an initial national approval as described above in any member state or Norway/Iceland/Lichtenstein. This will be termed the Reference Member State (RMS). After obtaining the initial approval, the RMS will obtain approval (if possible) from other member states according to the applicant's choice [termed Concerned Member States (CMS)] within a time frame of 90 days, but with limited scope for an applicant to resolve outstanding issues arising from the CMS opinions.

• A DCP resembles the MRP, involves fixed timelines (a full procedure may take up to about 210 days, and it may be terminated earlier if all countries agree on approval) for all steps, and several rounds of applicant responses for resolution of disagreement when a CMS signals a potential serious risk to public health.

In practice, most submissions nowadays follow the DCP route, because it more efficiently allows the applicant to respond to any concern the RMS or the CMS may have. An additional argument for using the DCP is that the first step of an MRP is the national approval step for which agencies are not always capable of adhering to their stated timelines. Thus, at the time of national submission, an applicant will not always know when the actual MRP can be initiated. A similar problem does not, in practice, exist for DCPs.

When some countries cannot approve a product in an MRP or DCP, this leads to a “referral,” which is outside the scope of this review. The reader is referred to article 29 of directive 2001/83.⁽¹⁾ Likewise, although an applicant has a theoretical opportunity to submit centrally (via the European Medicines Agency), this route falls outside the scope of this review.

There are no US equivalents to the European submission routes.

Studies

Europe

A guideline for demonstration of therapeutic equivalence for locally acting inhalation products came into force in 2009.⁽⁴⁾ It allows that an applicant delivers proof of therapeutic equivalence in an asthmatic population and extrapolates the claim to COPD patients without specific studies in the latter population. The guideline suggests that applicants follow a stepwise approach, as illustrated by Figure 1. In vitro similarity should be investigated first. If the in vitro data are sufficiently similar, approval can be granted; otherwise, the next step is evaluation of lung deposition and systemic exposure. If this step is sufficiently equivalent, approval can be granted; otherwise, the next and final step is a pharmacodynamic evaluation.

FIG. 1.

A graphical illustration of the stepwise approach implemented in the current EU guideline for demonstration of therapeutic equivalence. Note that this represents one—but not necessarily the only—stepwise approach. For example, after a failed step 1 (in vitro), an applicant might initiate a comparative safety exposure study before a comparative lung exposure study. PD, pharmacodynamics; PK, pharmacokinetics.

In the following, each of these steps is described in more detail.

Step 1: In vitro comparison

The requirements for pure in vitro approvals are as follows:

1. The product must contain the same API as the reference product (same salt, ester, etc.).

2. The dosage form must be identical.

3. The API must be in the solid state; crystalline differences cannot imply differences in dissolution.

4. Qualitative or quantitative differences should not influence product performance or affect inhalation behavior.

5. Qualitative or quantitative differences should not influence product safety or efficacy.

6. Inhaled volume through the device should be similar (15% difference allowed).

7. Handling must be similar.

8. Where relevant, device resistances should be similar (15% difference allowed).

9. Delivered dose should be similar.

10. Particle-size profiles as assessed by multistage impactors or impingers should be similar; a 90% confidence interval for the difference at four relevant stages or stage groups should be calculated. Equivalence limits are suggested to be 15%.

The guideline is not specific as to how these 10 requirements should be handled. For example, the choice of four relevant stages or stage groups is the applicant's responsibility.

For reference products that exist in multiple strengths, the guideline further opens up for extrapolation between strengths using in vitro data. If all of these requirements (or those relevant to the dosage form) are fulfilled, approval can be granted; otherwise, the next step (pulmonary deposition, systemic safety) needs to be investigated in vivo.

Step 2: Systemic safety and pulmonary deposition

For these purposes, pharmacokinetic studies are suggested. Two-dimensional imaging is briefly mentioned and allowed for pulmonary deposition, but for all practical purposes this is rarely the method of choice, and there are no details provided regarding such studies.

For pharmacokinetic studies, reference is made to the current European guideline on general investigation of bioequivalence,⁽⁵⁾ which covers the methodology for such studies regardless of dosage forms. A typical pharmacokinetic study follows the common two-sequence, two-treatment, two-period design with noncompartmental derivation of an area under the concentration–time curve (AUC) and maximum observed concentration (C_max). For analysis, ANOVA with subject, treatment, period, and sequence as fixed effects is typically used (note: parametric analysis is mandatory even if the residual is known to be non-Gaussian). The ANOVA residual and treatment effects are used to construct a 90% confidence interval for the test:reference ratio. The suggested acceptance range is 80% to 125%. Applicants may use designs with three periods or more to widen the acceptance range for C_max when the true intrasubject variability for the reference product is proven to be 30% or higher. Likewise, two-stage approaches may be allowed.

A pharmacokinetic study for systemic safety compares the total exposure arising form the use of the test and reference drug products, whereas a lung deposition study compares only the amount absorbed from the lung. To block gastrointestinal absorption, the guideline mentions, but does not mandate, charcoal. Healthy volunteers are not suggested: the studies should be carried out in the target population, but extrapolation from an asthma population to a COPD population is allowed. For APIs known to be subject to negligible oral bioavailability, systemic exposure might not be necessary when a pulmonary deposition study has been conducted.

If the requirements for systemic exposure and lung deposition are fulfilled, approval may be granted. Otherwise, the applicant should proceed to a pharmacodynamic study.

Step 3: Pharmacodynamics

Generally, a pharmacodynamic evaluation is suggested to be based on a relative potency assay (bioassay). This implies that both test and reference be tested at two nonzero doses and that a significant effect difference between the dose levels be observed (assay sensitivity). This allows for quantification of a relative potency for test:reference and construction of a confidence interval for the same. The acceptance range is suggested to be 67% to 150%. The choice of the endpoint is generally up to the applicant, but, in the absence of significant effect differences between the (positive, nonplacebo) dose levels, the bioassay's potency evaluation is invalid.

The guideline does not give very detailed design recommendations, but double-blind and randomized studies are generally suggested. Parallel designs, as well as crossovers, are acceptable as long as the choice is justified by the applicant.

Children and adolescents

The guideline contains a specific section for children and adolescents. Basically, in vivo studies may be waived if the in vitro similarity is extensive. This will either imply identity in terms of the device or, in case the test and reference devices differ, that the test device is known to work for children and “comparative in vitro data between the test and the reference product demonstrating comparable particle size distribution through the flow rate, pressure drop range and air volume clinically applicable to children, are available.” When the device is new, a handling study is recommended along with a package of in vitro data. Depending on the outcome for flow-rate dependency, further clinical studies may be necessary.

Specifically for adolescents, if therapeutic equivalence has been demonstrated for adults as well as children, the data may be interpolated to this population.

Combination products

The EU guideline requires that individual therapeutic equivalence be shown for all APIs. Interestingly, an applicant was able to obtain a marketing authorization through a DCP using Sweden as RMS for a combination product in 2011.⁽⁶⁾ The reader is encouraged to read the referenced publicly available assessment report to see an example of how the European guideline can be implemented in practice.

United States

Only a single adopted guideline that touches on the demonstration of bioequivalence for inhalation products exists, and it deals exclusively with in vitro aspects of bioequivalence testing for metaproterenol and albuterol (salbutamol) pressurized metered dose inhaler formulations.⁽⁷⁾ Although this guidance is from 1989, it is, in principle, still in force.

It recommends cascade impactor testing with characterization of deposition at individual stages, total deposition, geometric standard deviations, and mass median aerodynamic diameter. Optical microscopy should be used to determine crude particle-size distribution. Spray-pattern comparisons should be made (method up to the applicant), whereas plume geometry comparison is optional. Finally, data for in vitro potency, defined as the relative amount of delivered dose, should be submitted; the potency should reflect delivered doses from beginning, middle, and end of the canister's actuation life (not to be confused with shelf life).

In all cases, no success criterion is specified. Interestingly, a draft guidance document titled “Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action” was published in 2003 and described in greater detail how particle-size distribution profiles may be compared.⁽⁸⁾ Even though this document deals specifically with noninhaled formulations, is marked clearly with “Draft — Not for Implementation,” and was never superseded by an adopted guideline, some companies in practice try to use principles from this document for the in vitro comparison of inhalation formulations.

Additional Remarks and Discussion

There is, for most practical purposes, no guidance to lean on for approvals in the United States; in particular, none exists for the clinical portion of the development. For European submissions, a guideline is in place that allows delivery of a pivotal proof by three different ways (in vitro, pharmacokinetics, and pharmacodynamics). A further contrast is that, although generic submissions are possible in the United States, there is no current opportunity to obtain approval for a generic inhalation product in the legal sense. An EU product has to be submitted as a hybrid article (article 10.3), and this may negatively impact the chance of substitution being granted. The latter is generally a national matter in the EU.

As these products are generally difficult to develop, applicants may well wish to enter a dialogue with regulators before or during their developments. In the EU, dialogue with the regulators can be sought nationally or via the European Medicines Agency,⁽⁹⁾ but will, in either case, not be legally binding. Similar types of meetings are available at the US Food and Drug Administration (FDA).⁽¹⁰⁾ The EU and US regulators have agreed on principles to allow applicants to seek a “parallel scientific advice” when developments target the EU and US markets simultaneously.⁽¹¹⁾ Although it has been announced that “The expected advantages from such interactions are increased dialogue between the two agencies and sponsors from the beginning of the lifecycle of a new product, a deeper understanding of the bases of regulatory decisions, and the opportunity to optimize product development and avoid unnecessary testing replication or unnecessary diverse testing methodologies,” this wording does not necessarily imply that study designs or testing can be harmonized. In fact, the agencies further specify that “The goals for Parallel Scientific Advice procedures should focus on sharing information and perspectives, rather than specific harmonization of study or regulatory requirements, although if harmonization is achieved, that could be a beneficial outcome. (…) Each agency will provide their independent advice to the sponsor.” Thus, an applicant will, in most cases, have to make separate development plans for the two markets.

It should also be mentioned that comparators generally have to be sourced in the EU for EU approvals and in the United States for US approvals, implying that a single therapeutic (or bio-) equivalence study with one test and one reference product does not suffice for approval in both territories. Therapeutic (or bio-) equivalence studies with three treatments (the test product, one reference product sourced in the EU, one reference product sourced in the United States) are considered acceptable, though.

Although there is little formalized guidance from the FDA, they are in the process of developing these documents. There is, at present, no date for the issuance of the draft, but representatives from the FDA have indicated that a study is under way that seeks to investigate if assay sensitivity can be shown for corticosteroids when exhaled nitric oxide is used as the endpoint.⁽¹²⁾ Developers of products for the US market may benefit from a recent paper by employees of the FDA discussing in vitro aspects of comparative testing for dry powder inhalers,⁽¹³⁾ or by reading conference talks and proceedings from events arranged by the International Society for Aerosols in Medicine (ISAM), Product Quality Research Institute (PQRI), or International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS).^(14,15)

Footnotes

Author Disclosure Statement

The author is a former EU regulator, and was in charge of writing the 2009 guideline on proof of therapeutic equivalence for inhalation products. He is currently working as an independent consultant for innovator and generic companies. No funding was received for this work.

References

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Federal Food, Drug, and Cosmetic Act. SEC. 505 [21 USC §355] New DrugsAs amended 2008http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/FDCActChapterVDrugsandDevices/ucm108125.htm

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