Author byline as per print journal: Rana Musa Ali Al-ali “Malkawi”, MSc; Wesal Salem Al Haqaish, BPharm; Hayel Obeidat, MD

Submitted: 16 May 2018; Revised: 4 July 2018; Accepted: 5 July 2018; Published online first: 18 July 2018

Introduction

In Jordan, the Jordan Food and Drug Administration (JFDA) is the sole national authority that oversees drug safety and efficacy, and food safety and quality. JFDA strives to achieve both regional and international excellence in the control of food, drugs and related products. To ensure the safety and quality of food and its suitability for human consumption, together with the efficacy, quality and safety of medicine and related products, JFDA applies regulatory legislation based on scientific foundations and recognized global standards. It also has strong collaborations and cooperates with international partners and legislative bodies to ensure international standards are upheld. To help ensure a high level of health care and accessibility to it, JFDA is in charge of setting and implementing legislation, monitoring and surveillance, and raising public awareness.

As part of JFDA, the Drug Directorate is responsible for medicines and their registration in Jordan. This is the only official body responsible for medicines throughout their life cycle, starting from active pharmaceutical ingredients and going through all developmental phases and trials until medicines are ready to be used by patients as finished products. The Drug Directorate is keen to provide both innovative and generic medicines within a reasonable period of time, after ensuring their safety, quality and efficacy.

Biopharmaceutical regulation in Jordan: a history

JFDA was founded in 2003. In 2004, JFDA issued criteria for registration and re-registration of all drugs. In 2009, it was decreed by the higher committee of drug and pharmacy at JFDA that all drug applications submitted to JFDA must follow the International Council for Harmonisation’s Common Technical Document (ICH CTD) format [1, 2], the CTD file is organized into five modules. Module 1 is region specific and an administrative module with country specific requirements; and Modules 2, 3, 4 and 5 are intended to be common for all regions and are the CTD internationally required modules.

In 2013, JFDA issued draft guidance on biosimilar registration in Jordan. This was in response to the rising use and concerns over biosimilar drugs following the expiration of some major originator drug patents, and the emergence of biosimilars in European and international markets. Following its release for comments and review by all concerned parties and stakeholders, the guidance was finally published as the official guideline for biosimilar registration in Jordan on 5 May 2015 [3], and JFDA defined biosimilarity according to its own guidelines [3]. Nonetheless, JFDA evaluators relied on the published guidelines from the European Medicines Agency (EMA) [4] to evaluate biosimilars applications submitted during the period of 2009 to 2015.

At the time that JFDA developed its guidelines on biosimilar registration, EMA had the most well-developed regulatory framework for biosimilars [4]. This consists of general guidelines applicable to all biosimilars as well as specific guidelines, which set the basis for defining the registration requirements for biosimilars. As such, JFDA biosimilars registration guidelines are an adapted version of EMA biosimilar approach and any updates to the current EMA biosimilar guidelines are subsequently adopted by JFDA. In addition, JFDA reserves the right to request any additional information or material, or define specific conditions in order to ensure the safety, efficacy and quality of biosimilars.

Biosimilars under the JFDA registration guidelines

JFDA definition of a biosimilar
JFDA defines a biosimilar as a biological medicinal product that is similar to the Reference Biological Product (RBP) in terms of quality, safety and efficacy, and contains a version of the active substance that is similar, in molecular and biological terms, to the active substance of the RBP [3]. On the other hand, according to JFDA, the RBP is the innovator biological medicinal product either already approved/registered in the reference countries in the EU (via the centralized procedure), Australia, Canada, Japan, the US, and/or Jordan. This product should be registered on the basis of a complete dossier (full quality, safety and efficacy).

The definition of a biosimilar sets the road map for the requirements to be submitted within the five modules of the application, of which the most important requirement is the comparability exercise. The comparability exercise must demonstrate proof of similarity in terms of quality, safety and efficacy between the RBP and the biosimilar product. Also, it is an additional element to the requirements of the quality dossier and should be dealt with separately when presenting the data. The comparability exercise is a stepwise development process that compares the physicochemical, biological and clinical aspects of the biosimilar and the RBP.

The purposes of the JFDA biosimilar registration guidelines are to:

• Provide assistance to applicants (industry) on how to comply with the regulations
• Introduce the concept of biosimilars
• Provide a baseline of scientific comparison between the biosimilar and the RBP (the comparability requirements) with regards to quality, safety and efficacy
• Identify the level of clinical data needed to evaluate and approve the biosimilar
• Focus on the quality assessment of the biosimilar, with a head-to-head comparison RBP with full characterization of quality parameters using state-of-the-art techniques and analytical methods or procedures
• Focus on marketing safety studies to monitor any potential differences in safety including immunogenicity between the biosimilar and the RBP that become apparent after a biosimilar enters the market
• Specify details to ensure traceability with regards to pharmacovigilance for biosimilars

JFDA biosimilars pharmacovigilance plan and risk management plan [3]
JFDA guidelines for biosimilars also emphasizes the need for a pharmacovigilance (PV) plan and a risk management plan (RMP) for biosimilar products at the time of submission.

The PV plan should be designed to monitor and detect both known inherent safety concerns and potentially unknown safety problems that may have resulted from the impurity profiles of a biosimilar, or may have been undetected in pre-market testing or otherwise not expected.

Any post-marketing RMP should include detailed information on a systematic testing plan for monitoring immunogenicity of the biosimilar post-marketing, and to take into account identified and potential risks associated with the use of the reference product and, if applicable, additional potential risks identified during the development programme of the biosimilar and should detail how these issues will be addressed in post-marketing follow-up [3]. There is special focus on the post-marketing safety studies in order to monitor any potential differences in the safety and efficacy between the biosimilar and the RBP that becomes apparent once the biosimilar has entered the market, Here, details must be specified to ensure traceability of biosimilars, to facilitate effective PV monitoring and tracing of adverse safety events and to prevent inappropriate substitution, the specific medicinal product (innovator or biosimilar) prescribed by the treating physician and dispensed to the patient should be clearly identified. Therefore, all biosimilars should be distinguishable by name, i.e. assigned a brand name explicitly, so every medicine will either have invented (trade) name, or the name of the active substance (according to the current International Nonproprietary Name (INN) and Word Health Organization system [5]) together with the company name/trademark.

The approved name, together with the batch number, the country of origin and manufacturer name are important for clear identification to facilitate adverse drug reaction reporting and monitoring of the use of the medicine.

For the purpose of gathering additional information about a product’s safety and efficacy, or optimal use, JFDA requires that a post-marketing surveillance study (phase IV) be conducted in Jordan as a post-registration requirement for biosimilars. An interim report based on the first 50 patients should be provided to JFDA so that it is up-to-date on spontaneous adverse events reports.

Biosimilar application evaluation in Jordan

Biosimilar applications in Jordan are reviewed thoroughly and comprehensively by JFDA’s Technical Committee for the registration of new drugs. Members of the committee are chosen according to Jordan’s Drug and Pharmacy Law [6], these members are chosen for the purpose of reviewing the contents of new drugs registration files and finally approving them. This committee is comprised of members from within JFDA and external assessors who are highly qualified technical scientists from both the public and private sectors.

During the evaluation of the biosimilar dossier, samples of the biosimilar drug are sent to the Drug Control Laboratory Directorate of the JFDA for analysis. In addition, the manufacturing sites responsible for any step in the manufacturing of the biosimilar product, starting from the active biological substance storage and use of the Working Cell Bank, and ending with the finished product, as well as the site responsible for the batch release of the finished biosimilar product, are all accredited and approved by JFDA. This is done via the JFDA’s Sites Accreditation Committee, this is mentioned in the Drug and Pharmacy Law in Arabic on the JFDA website [6], information in Arabic is available from the authors upon request. Under certain circumstances, as laid out in the relevant JFDA guidelines, an on-site inspection visit can be carried out by a team of experts from JFDA and external experts, before issuing final approval and accreditation of sites.

An overview of the biosimilar regulation and approval by JFDA

The JFDA pathway for biosimilars registration is a comprehensive, elaborate and scientific pathway that covers all aspects of the technical dossier as well as the rigorous comparability exercise and extends accreditation of analytic and manufacturing sites. This pathway ensures that biosimilars registered in Jordan have been authorized following a strict regulatory process comparable to what is required for approval of biosimilars by EMA.

The JFDA pathway is in line with the most up-to-date international regulations regarding the review and registration of medicines, especially those of EMA and the US Food and Drug Administration. It is also committed to recruiting well-trained employees and experts form all fields. This results in the supply of reliable, safe and effective drugs.

Competing interests: The authors declared that there is no potential conflict of interest.

Provenance and peer review: Commissioned; externally peer reviewed.

Authors

Rana Musa Ali Al-ali “Malkawi”, MSc, Head of Clinical Studies Department

Wesal Salem Al Haqaish, BPharm, Drug Directorate Director

His Excellency Hayel Obeidat, MD, Ophthalmologist, Director General

Jordan Food and Drug Administration 11181/811951 Amman, Jordan

References
1. Jordan Food and Drug Administration. Drugs registration criteria; check list regarding CTD submission for drug registration purposes [homepage on the Internet]. [cited 2018 Jul 4]. Arabic. Available from: http://www.jfda.jo/EchoBusV3.0/SystemAssets//PDF/AR/LawsAndRegulation/Drug/RegisterSection/%D8%A3%D8%B3%D8%B3%20%D8%AA%D8%B3%D8%AC%D9%84%D9%84%20%D8%A7%D9%84%D8%AF%D9%88%D8%A7%D8%A1%20%D9%84%D8%B3%D9%86%D8%A9%202015%20%D9%88%D8%AA%D8%B9%D8%AF%D9%8A%D9%84%D8%A7%D8%AA%D9%87%D8%A7.pdf
2. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. M4: The Common Technical Document [homepage on the Internet]. [cited 2018 Jul 4]. Available from: http://www.ich.org/products/ctd.html
3. Jordan Food and Drug Administration. Guideline for registration of biosimilars in Jordan [homepage on the Internet]. [cited 2018 Jul 4]. Arabic. Available from: http://www.jfda.jo/EchoBusV3.0/SystemAssets/PDF/AR/LawsAndRegulation/Drug/RegisterSection/10_303.pdf
4. European Medicines Agency. The European Medicines Agency’s scientific guidelines on biosimilar medicinal products help medicine developers prepare marketing authorisation applications for human [homepage on the Internet]. [cited 2018 Jul 4]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c=Overarching%20biosimilar%20 guidelines
5. World Health Organization. International Nonproprietary Names [homepage on the Internet]. [cited 2018 Jul 4]. Available from: http://www.who.int/medicines/services/inn/en/
6. Jordan Food and Drug Administration. Jordan Drug & Pharmacy Law number 12 issued in 2013 [homepage on the Internet]. [cited 2018 Jul 4]. Available from: http://www.jfda.jo/EchoBusV3.0/SystemAssets/PDF/AR/LawsAndRegulation/Drug/DrugDirectorate/%D9%82%D8%A7%D9%86%D9%88%D9%86%20%D8%A7%D9%84%D8%AF%D9%88%D8%A7%D8%A1%20%D9%88%D8%A7%D9%84%D8%B5%D9%8A%D8%AF%D9%84%D8%A9.pdf

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