Abstract
Independent development of regulatory frameworks in Australia, Europe and the USA has led to differences in their regulatory approach to biologics (or biologicals). Some of these were favourable for the conduct of early clinical trials (i.e. TGA CTN and CTX). Others have been affected by external factors (i.e. UK membership in the EU) or have expanded their scope (i.e. CBER emergence within the FDA). Recently efforts have been made to harmonise the three frameworks via joint guidances to industry and researchers and memoranda of understanding and cooperation among the regulatory bodies from the regions. We present our own experience in manufacturing and use of human placenta-derived mesenchymal stromal cells (hpMSC) in phase 1 clinical trials conducted in Australia according to the new Biologicals Framework established by Therapeutic Goods Administration (TGA) as from 1 July 2011. We also present similarities and differences with some other regulatory frameworks (USA and EU) that may be of interest to us in the future.
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17.1 Introduction
Taking newly created biomedical discoveries from the bench to the bedside has proven to be a highly challenging and costly exercise. It has been defined as Translational Research and recognised by researchers, funding agencies and, recently, by regulatory agencies across the globe, as an imminent need. Success in translational research requires not only highly trained experts and complex skill sets within a team but also an understanding of the application of data in different regulatory frameworks. Independent development of regulatory authorities in Australia, Europe and the USA has led to differences in their approach to pharmaceutical manufacturing as well as regulation of biologic drugs (or biologicals). Some of these frameworks were favourable for the conduct of early clinical trials with minimal supporting data; others have been affected by external factors or have expanded their scope through the years. Recent efforts have been made to harmonise the three frameworks.
Although therapeutics derived from biological sources have been subjected to regulatory oversight for some time (i.e. monoclonal antibodies) the biologic products used in transplantation procedures have historically been exempted from this oversight. The unique source of the “active ingredients” renders cell and tissue therapies difficult to be assessed by the traditional regulatory system which has been geared to pharmaceutical quality control. It has been recognised that therapeutic claims for biologics needed to be supported. New considerations have led the existing regulatory agencies of the developed world to propound new regulatory approaches for biologics (or biologicals). Furthermore, in addition to considerations of regulation of medicines and medical devices manufactured in the traditional manner, the regulation of cell and tissue products is closely linked to sensitive areas of public health policy and funding. This positions regulators in a challenging position as they attempt to reconcile their roles as independent assessors with public health needs and perceptions.
Cell and tissue biologic therapies must be developed and manufactured through disciplined and specific mechanisms, even when full compliance with traditional concepts of pharmaceutical manufacturing practice is not possible, particularly for life-saving therapies. These systems incorporate considerations of risk–benefit ratios and include mechanisms for transparent and accountable release of products, usually based on urgent medical need.
This chapter explores regulatory considerations applicable to manufacturing and use of human placenta-derived mesenchymal stromal cells (hpMSC) in clinical trials in Australia and comparison to USA and European regulatory frameworks. Sections 17.2, 17.3 and 17.4 present the regulatory frameworks provided by the Therapeutic Goods Administration (TGA), the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in Australia, the USA and the EU, respectively. In Sect. 17.5 we present our own experience in manufacturing and use of hpMSC in phase 1 clinical trials conducted in Australia. Section 17.6 gives an overview of information required in applications for clinical trials and ICH GCP. Finally, in Sect. 17.7 a comparison is given taking into account regional drug regulations and clinical trial approval processes.
17.2 Therapeutic Goods Administration: Australia
In Australia the Therapeutic Goods Administration (TGA) was established in 1990 as a division of the Commonwealth Department of Health and Aged Care. Its charter is to ensure that therapeutic goods are assessed and controlled for safety, quality and efficacy at a standard equal to that of the comparable countries. Its role is also to provide the Australian community with access, within reasonable time, to modern therapeutic advances. It is based on the Therapeutic Goods Act, 1989 (the Act), which is approved by the Federal Parliament and establishes a uniform, national system of regulatory control to ensure the quality, safety, efficacy and timely availability of therapeutic goods for human use. Although there are certain applicable territories/state regulations involved, responsibility for the regulatory control lies with the TGA as the national regulatory authority [1–5].
The TGA controls the supply of therapeutic goods through three main processes (pre-market evaluation and approval, licencing of manufacturers and post-market surveillance).
Therapeutic goods for human use that are imported, manufactured in Australia, supplied by a corporation, supplied interstate or to the Commonwealth, or exported must be included in the Australian Register of Therapeutic Goods (ARTG) unless specifically exempted. Access to unapproved therapeutic goods (items exempted from entry to ARTG) is controlled through a few different mechanisms: Special Access Scheme (Cat. A and B), Clinical Trials (CTN and CTX Schemes), authorised prescriber/s, and importation for personal use [3–5]. Human Research Ethics Committees (HREC) also play an important role in the regulation of the supply of unapproved goods under the Act in relation to Clinical Trials (both CTN and CTX schemes), the Special Access Scheme and approval of Authorised Prescribers [2]. Separate branches of the TGA are responsible for prescription drug evaluation, regulation of therapeutic advice, over-the-counter drug regulations and compliance issues, and general administration. Another branch consists of the TGA Laboratories (previously the National Biological Standards Laboratory) [3–5].
The TGA regulatory framework is based on a risk management approach to ensure public health and safety, while at the same time trying to free industry from any unnecessary regulatory burden. Australian manufacturers of all medicines must be licenced under Part 4 of the Act, and their manufacturing process must comply with the principles of Good Manufacturing Practice (GMP). In assessing the risk, factors such as the strength of a product, side effects, potential harm through prolonged use, toxicity and the seriousness of the medical condition for which the product is intended to be used are all taken into account. Medicines assessed as having a higher level of risk (prescription medicines and some non-prescription medicines) are evaluated for quality, safety and efficacy and registered on the ARTG. Medicines having a lower risk (i.e. over-the-counter medicines and complementary medicines including vitamins) are assessed for quality and safety. Once approved for marketing in Australia, medicines are included in the ARTG and can be identified by the AUST R number (for registered medicines) or an AUST L number (listed medicines) that appears on the packaging of the medicine [1–5].
An important part of TGA control and activities is through Clinical Trials. There is no requirement that application to the TGA to market medicines must contain data from clinical trials conducted in Australia. However, the Australian CTX (Clinical Trial Exemption) and CTN (Clinical Trial Notification) Schemes offer considerable benefits by providing the momentum to research and developing new medicines locally. The choice of which TGA Clinical Trial Scheme (CTN or CTX) to follow lies primarily with the sponsor (sponsoring organisation) and then with HREC. Notification under the CTN or application under the CTX is required for any medicine not entered on the ARTG (including a new formulation of an existing product or any new route of administration), or the use of a registered medicine beyond the conditions of its marketing approval (including new indications extending the use of the product to a new population group and the extension of doses or duration of treatment outside of the approved range) [1–5].
There are a number of Regulatory Requirements, Standards and Guidelines applicable to novel cell therapies used in Clinical Research in Australia (Table 17.1) [25–29]. The new Biological Framework was established by the Australian Therapeutic Goods Administrations (TGA) after long and careful consideration (http://www.tga.gov.au/bt/hct.htm) to improve the regulation of human tissue and cellular therapies and to provide improved clarity by applying different levels of pre-market regulation to biological products based on the risks associated with the use of each product (http://www.tga.gov.au/ct/index.htm#med). Human placenta-derived mesenchymal stromal cells (hpMSC) are categorised as Class 3 products within the new framework. As a result, any clinical trial utilising Class 3 hpMSC can be conducted under the TGA’s Clinical Trial Notification (CTN) Scheme. The CTN scheme is designed to combine rapid approval of clinical trial protocols with ongoing monitoring and supervision by HRECs acting in accordance with nationally agreed guidelines developed by the National Health and Medical Research Council (NHMRC). It is important to note that the TGA does not review any data relating to the trial under this scheme (http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ComplianceActivities/Enforcement/CompliancePrograms/ucm095207.htm).
17.2.1 TGA Exemptions and “Special Schemes” for Investigational Drugs (Including Biologicals)
Access to unapproved therapeutic goods (items exempted from entry to ARTG), other than Clinical Trials (CTN and CTX Schemes) is controlled in Australia by TGA through several mechanisms: Special Access Scheme (Cat. A and B), authorised prescriber/s, and importation for personal use [3–5].
Under the Therapeutic Goods Act (the Act), therapeutic goods/medicines can be exempted to allow for their use for experimental purposes in humans (clinical trials). The same regulatory Act (mostly in Sections 18 and 19 of the Act) allows some other exemptions, such as exemption of therapeutic goods by the Federal (National) Minister of Health, if the Minister is satisfied that, in the national interest, the goods may be stockpiled as quickly as possible in order to deal with a potential threat to public health (that may be caused by a possible future emergency) or to deal with an actual threat to public health (caused by an emergency that has occurred). According to the Act, it is possible to allow exemptions for special and experimental uses, if the Secretary of the Federal Department of Health by notice in writing, grants an approval to a person for use in the treatment of another person, or solely for experimental purposes in humans (and such approval may be given subject to such conditions as are specified in the notice of approval). Medicines (except for gene therapy) that are dispensed or extemporaneously compounded for a particular person can be exempt from TGA regulation. Similar exemptions may apply to medicines individually dispensed by traditional Chinese medicine and homoeopathic practitioners [3–5].
According to the Act, it is possible to allow exemptions due to unavailability of therapeutic goods. In this case the Secretary may grant approval, by notice in writing, for registered goods that could act as a substitute for goods that are unavailable, goods that are in short supply, or registered goods that could act as a substitute for goods that not exist. All of these actions under specified circumstances may require provision of particular information about the goods storage, handling, use, monitoring, records, and disposal of unused goods [5].
17.3 Food and Drug Administration (CDER vs. CBER): USA
The Centre for Drug Evaluation and Research (CDER) and its Office of New Drugs are divisions of the Food and Drug Administration (FDA) responsible for investigating the quality, efficacy and safety of drug products, including clinical trials materials, in the USA. CDER is divided into five subdivisions (known as Offices of Drug Evaluation or ODEs), each responsible for a particular therapeutic area of drug control [6–8].
The Centre for Biological Evaluation and Research (CBER) regulates biological and related products including blood, vaccines, allergens, tissues, and cellular and gene therapies. Biologics, in contrast to drugs that are chemically synthesised, are derived from living sources (such as humans, animals and microorganisms), are not easily identified or characterised and many are manufactured using biotechnology. These products often represent cutting-edge biomedical research and, in time, may offer the most effective means to treat a variety of medical illnesses and conditions that presently have few or no other treatment options [6–8]. CBER’s review of new biological products, and for new indications for already approved products, requires evaluating scientific and clinical data submitted by manufacturers to determine whether the product meets CBER’s standards for approval. After a thorough assessment of the data, CBER makes a decision based on the risk–benefit for the intended population and the product’s intended use. CBER’s authority resides in the Public Health Service Act and in specific sections of the Food Drug and Cosmetic Act [9–13].
The American system for clinical trials approval bears some similarities to that in Australia, but there are some notable exceptions. Unlike the Australian system of TGA approval through the CTX scheme and HREC approval through a CTN, all clinical trials applications in the USA are considered by the FDA. Simply stated, the American system does not allow an HREC to approve a clinical trial in isolation, as can occur under the Australian system. The formal application for a clinical trial in the USA is known as an Investigational New Drug application (IND). The information contained in the IND is similar to that which might constitute a CTX application in Australia (i.e. biological and toxicological information, chemistry and manufacturing information and clinical trials protocol and investigator information) [9–13].
17.3.1 FDA Exemptions and “Special Schemes” for Investigational Drugs (Including Biologics)
Access to unapproved drugs in the USA can occur through a number of legal mechanisms (apart from clinical trials), such as a special exception or compassionate exemption, an emergency Investigational New Drug (IND), and a Treatment IND [6–9].
If the eligibility criteria in a study protocol are not suitable for a particular patient, it may still be possible to get that patient treated according to a special exception (also called compassionate exemption). This process depends on the decision of investigator and sponsor, and requires written request to the FDA, modifying the consent form and obtaining permission from the local institutional review board (IRB) (ethical committee). The requesting letter should state the rationale for the exception and provide a brief patient history. It is sent as general correspondence to the appropriate IND application [9].
There is also an exception available through a mechanism called a treatment IND. Under this program, a sponsor of a drug that has shown clinical promise and is still under review by the FDA may charge for the drug during the review process if permission is granted by the FDA. This provides expanded access to the drug prior to commercial distribution [9]. According to the Code of Federal Regulation (21CFR312.34), in general, a drug that is not approved for marketing may be under clinical investigation for a serious or immediately life-threatening disease condition in patients for whom no comparable or satisfactory alternative drug (or other therapy) is available. During the clinical investigation of the drug, it may be appropriate to use it in the treatment for patients not in clinical trials (in accordance with specific IND application). The purpose is to facilitate the availability of promising new drugs to desperately ill patients as early as possible, and also to gain additional data on the drug’s safety and effectiveness. There are specific requirements applicable to certain phases of the trials (Phases 2 and 3), and specific criteria (i.e. if the drug is intended to treat a serious or immediately life-threatening disease, and there is no comparable or satisfactory alternative drug) [6–9].
17.3.2 Outline of the FDA Framework for Human Cells, Tissues, and Cellular and Tissue-Based Products
In the early 1990s, the Center for Disease Control and Prevention (CDC) reported that human immunodeficiency virus (HIV) had been transmitted through transplantation of human tissue. Information was also reported which suggested that potentially unsafe tissue was being imported into the USA for transplantation into humans. Prompted by reports that potentially unsafe bone was being imported, the Commissioner of Food and Drugs ordered an immediate investigation. Information resulting from this investigation identified an immediate need to protect the public health from the transmission of HIV and hepatitis B and C through transplantation of unsuitable tissue. Concerns that disease transmission could occur, coupled with information derived from these investigations, prompted the Food and Drug Administration (FDA, the Agency) to publish an interim rule in December 1993 that specifically required certain communicable disease testing, donor screening, and record-keeping for human tissue intended for transplantation. A final rule was issued in July 1997 [14]. The FDA chose to regulate tissues under the legal authority of Section 361 (Sec. 361) of the Public Health Service Act (hereafter, PHS Act) [42 USC 264]. This section authorises the Surgeon General, with the approval of the Secretary, Department of Health and Human Services, to make and enforce such regulations as judged necessary to prevent the introduction, transmission, or spread of communicable diseases from foreign countries into the USA or from State to State. Section 361 of the PHS Act focuses on preventing the introduction, transmission and spread of communicable diseases [14].
In 1997, the agency announced its plans for human cells, tissues, and cellular and tissue-based products (HCT/Ps) in two documents: “A Proposed Approach to the Regulation of Cellular and Tissue-Based Products” (62 FR 9721, March 4, 1997) and “Reinventing the Regulation of Human Tissue”. FDA requested written comments on its proposed approach and, on March 17, 1997, held a public meeting to solicit information and views from the interested public. Since that time, the Agency has published three final rules and one interim final rule to implement aspects of the proposed approach [14]. On January 19, 2001, the FDA issued regulations to create a new unified system for registering HCT/P establishments and for listing their HCT/Ps (registration final rule, 66 FR 5447). The registration rule became effective in two stages. The first effective date, April 4, 2001 was applicable to establishments that were already regulated under 21 CFR Part 1270. The second effective date was originally January 21, 2003, and was applicable to establishments that manufacture HCT/Ps currently regulated as biological products, drugs, or devices, haematopoietic stem cells from peripheral and cord blood, and reproductive cells and tissues. On January 21, 2003, the FDA announced that the registration requirements for these establishments would be further delayed until January 21, 2004 [14].
On January 27, 2004, the FDA issued an interim final rule to except human dura mater and human heart valve allografts from the scope of that definition until all of the tissue rules became final. On May 25, 2004, the FDA promulgated regulations requiring most cell and tissue donors to be tested and screened for relevant communicable diseases (donor-eligibility final rule, 69 FR 29786). On November 18, 2004, FDA issued regulations that require establishments that manufacture HCT/Ps to comply with Current Good Tissue Practices (CGTP), which would include, among other things, proper handling, processing, labelling and record-keeping procedures. The regulations require each establishment to maintain a quality program to ensure compliance with CGTP. In addition, with the implementation of CGTPs, human dura mater and human heart valve allografts are now included in the scope of HCT/Ps regulated under the 21 CFR 1271. On May 25, 2005 the FDA published an interim final rule to revise certain regulations regarding the screening and testing of HCT/P donors and related labelling (interim final rule, 70 FR29949). This action was taken by the FDA in response to comments from interested persons regarding the impracticability of complying with certain regulations as they affect particular HCT/Ps [14].
The CGTP and other regulations are contained in 21 CFR Part 1271, along with provisions relating to establishment registration. These regulations will apply to HCT/Ps recovered on or after the rule’s effective date, May 25, 2005. HCT/Ps that were recovered before the effective date of the new rules are subject to 21 CFR 1270, and subparts A and B of Part 1271, as appropriate. In addition, 21 CFR Part 1271 subparts A, B, C, F, 21 CFR 1271.150(c), and 21 CFR 1271.155 of subpart D apply to reproductive HCT/Ps. The new Part 1271 is made up of six subparts:
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General provisions pertaining to the scope and purpose of Part 1271, as well as definitions.
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Registration and listing procedures.
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Provisions for the screening and testing of donors to determine their eligibility.
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Current Good Tissue Practice (CGTP) requirements.
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Certain labelling and reporting requirements.
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Inspection and enforcement provisions.
21 CFR 1271.10(a) sets out the criteria that form the foundation of our tiered, risk-based approach to regulating HCT/Ps. HCT/Ps that meet all of these criteria are subject only to regulation under section 361 of the PHS Act. These HCT/Ps are subject to the regulations in Part 1271, and no pre-market approval is required. HCT/Ps that do not meet all of the criteria in 21 CFR 1271.10(a) are regulated as drugs, devices and/or biological products. The HCT/Ps are subject to the regulations specific to drugs, biological products, or medical devices, in addition to applicable sections of Part 1271. Bone (including demineralised bone), Ligaments, Tendons, Fascia, Cartilage, Ocular Tissue (Corneas and Sclera), Skin, Arteries and Veins (except umbilical cord veins), Pericardium, Amniotic membrane (when used alone, without added cells for ocular repair), Dura mater, Heart valve allografts, Semen, Oocytes, Embryos and Haematopoietic stem/progenitor cells derived from peripheral and cord blood [14].
The above HCT/Ps are regulated solely under section 361 of the PHS Act and the regulations in 21 CFR Part 1271 if they meet all of the following criteria:
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Minimally manipulated; -Intended for a homologous use only as reflected by the labelling, advertising, or other indications of the manufacturer’s objective intent; -Not combined with another article (except for water, crystalloids, or a sterilising, preserving, or storage agent, if the addition of the agent does not raise new clinical safety concerns with respect to the HCT/P); and Either:
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Do not have a systemic effect and are not dependent upon the metabolic activity of living cells for the primary function; OR
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Have a systemic effect or are dependent upon the metabolic activity of the other cells for the primary function, AND:
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Are for autologous use; -Are for allogeneic use in a first- or second-degree relative; OR -Are for reproductive use [14].
Those HCT/Ps that do not meet all 21 CFR 1271.10(a) criteria and are regulated as drugs, devices, or biological products are covered under separate compliance programs [14], such as:
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Blood and Blood Products are covered under CP 7342.001 “Inspection of Licenced and Unlicenced Blood Banks, Brokers, Reference Laboratories, and Contractors”; and CP 7342.002 “Inspection of Source Plasma Establishments”
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HCT/Ps that do not meet all 21 CFR 1271.10(a) criteria, and are regulated as Medical Devices are covered under CP 7382.845 “Inspection of Medical Device Manufacturers”
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HCT/Ps that do not meet all 21 CFR 1271.10(a) criteria, i.e. Autologous, Allogeneic, or Xenogeneic Cells whose biological characteristics have been altered (propagate, pharmacologically treated, etc.); Ex Vivo and Gene Therapy products are regulated as biological drugs and are covered under CP 7345.848 “Inspection of Biological Drug Products”
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HCT/Ps recovered before May 25, 2005 and regulated under 21 CFR 1270 and subparts A and B of Part 1271 are covered under CP 7341.002A “Inspection of Tissue Establishments”
HCT/P establishments must follow CGTP requirements to prevent the introduction, transmission, or spread of communicable diseases by ensuring that the HCT/Ps do not contain communicable disease agents, that they are not contaminated, and that they do not become contaminated during manufacturing [14]. The following are Core CGTP requirements as referenced in 21 CFR 1271.150(b) [14]:
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Requirements relating to facilities (21 CFR 1271.190(a) and (b))
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Requirements relating to environmental controls (21 CFR 1271.195(a))
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Requirements relating to equipment (21 CFR 1271.200(a))
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Requirements relating to supplies and reagents (21 CFR 1271.210(a) and (b))
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Requirements relating to recovery (21 CFR 1271.215)
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Requirements relating to processing and process controls (21 CFR 1271.220)
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Requirements relating to labelling controls (21 CFR 1271.250(a) and (b))
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Requirements relating to storage (21 CFR 1271.260(a)–(d))
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Requirements relating to receipt, pre-distribution shipment, and distribution of an HCT/P (21 CFR 1271.265(a)–(d)).
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Requirements relating to donor eligibility determinations, donor screening and donor testing (sections 1271.50, 1271.75, 1271.80 and 1271.85).
All establishments engaged in manufacture (as defined in 21 CFR 1271.3(e)) of an HCT/P must register with and submit to the FDA, a list of each human tissue product manufactured unless being exempt by 21 CFR 1271.15. New establishments must register and list within 5 days of beginning operations [14]. CBER maintains an alphabetic listing of currently registered HCT/P establishments that is accessible on the CBER Internet web site at http://www.fda.gov/cber/tissue/hctregestabl.htm [14].
17.4 European Medicines Agency: Europe
The European Medicines Agency (formerly known as EMEA, now abbreviated to EMA) is a decentralised body of the European Union with headquarters in London. The European Medicines Agency is headed by the Executive Director, who is appointed by the Agency’s Management Board. The Agency is divided into five Units, each with between two and four sectors. Most sectors are further divided into a number of sections. In addition to its staff, EMA is composed of a Management Board and six scientific committees. The committees and working parties (some including patients’ and doctors’ representatives) are supported by more than 4,500 European experts and conduct the main scientific work of the Agency [15, 16].
The EMA’s main responsibility is the protection and promotion of public and animal health, through the evaluation and supervision of medicines for human and veterinary use. The European Medicines Agency coordinates the evaluation and supervision of medicinal products throughout the European Union. The European Medicines Agency brings together the scientific resources of some 40 national competent authorities in 30 EU and EEA-EFTA countries (Iceland, Liechtenstein and Norway). It cooperates closely with international partners, reinforcing the EU contribution to global harmonisation [15, 16].
The EMA began its activities in 1995, when the European system for authorising medicinal products was introduced, providing for a centralised and a mutual recognition procedure. The Agency has a role in both, but is primarily involved in the centralised procedure. Where the centralised procedure is used, companies submit one single marketing authorisation application to the Agency. A single evaluation is carried out through the Committee for Medicinal Products for Human Use (CHMP) or Committee for Medicinal Products for Veterinary Use (CVMP). If the relevant Committee concludes that quality, safety and efficacy of the medicinal product is sufficiently proven, it adopts a positive opinion. This is sent to the Commission to be transformed into a single market authorisation valid for the whole of the European Union [15, 16].
The Committee for Advanced Therapies (CAT) was established in accordance with Regulation (EC) No. 1394/2007 on advanced therapy medicinal products (ATMPs). It is a multidisciplinary committee, gathering together some of the best available experts in Europe to assess the quality, safety, and efficacy of ATMPs, and to follow scientific developments in the field. The main responsibility of the CAT is to prepare a draft opinion on each ATMP application submitted to the European Medicines Agency, before the Committee for Medicinal Products for Human Use (CHMP) adopts a final opinion on the granting, variation, suspension or revocation of a marketing authorisation for the medicine concerned. At the request of the EMA Executive Director or of the European Commission, an opinion is also drawn up on any scientific matter relating to ATMPs [15, 16].
The Regulation on Advanced Therapies (Regulation (EC) 1394/2007) defines advanced therapy medicinal products (ATMPs) such as gene therapy, somatic cell therapy and tissue engineered products in Article 2 of Regulation (EC) 1394/2007. Article 29 of the same Regulation foresees that ATMPs on the EU market in accordance with national or EU legislation will have to comply with the new legislation by 30 December 2011 for ATMPs other than tissue engineered products or 30 December 2012 for tissue engineered products. In EMA announcement from July 2008, the European Medicines Agency raised awareness among manufacturers, companies and hospitals having ATMPs legally on the market that these products will have to undergo a marketing authorisation procedure (in line with Regulation (EC) 1394/2007), unless they are exempted in accordance with Article 28 (2) of the same Regulation. This exemption applies to ATMPs prepared on a non-routine basis according to specific standards, and used within the same EU member state in a hospital under the exclusive professional responsibility of a medicinal practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient.
Further definition of advanced therapy medicinal products (ATMPs) and a set of specific instructions (i.e. for somatic cell therapy medicinal and tissue engineered products, for advanced therapy medicinal products containing devices or for gene therapy medicinal products) were provided in the Commission Directive 2009/120/EC amending the Directive 2001/83/EC [15, 16].
The European Medicines Agency’s Committee for Advanced Therapies (CAT) has unveiled a Work Programme to 2015, intended to help increase the number of advanced therapy medicinal products (ATMPs) that make it from early research stage to the market. With this 5-year program, the CAT aims for an environment that encourages the development of ATMPs while recognising that the traditional regulatory framework for medicines does not currently fully address the needs of companies and organisations (including hospitals) that develop these medicines. The training and early dialogue between the CAT and relevant stakeholders play a central role. In this context, the CAT will also look at the current regulatory framework and at how it can be made more accessible for small and medium-sized enterprises, academia, patient groups, hospitals, charity foundations, and trusts developing ATMPs. Proposed actions are also taking into account that new and emerging science is an important driver for progress and change in the health-care field [15, 16].
In March 2011 an EMA-FDA pilot program for parallel assessment of Quality by Design applications was established. The assessment of Marketing Authorisation Application (MAAs)/New Drug Applications (NDAs) including Quality by Design (QbD) or enhanced pharmaceutical development approaches, requires a good understanding of statistical, analytical and risk assessment development methods that have not been systematically used by pharmaceutical industry or regulators in the past. This program provides advice to applicants on the background and objectives of the pilot study, as well on the operational steps that will be taken to coordinate a parallel review and related GMP inspections by EMA and FDA, following ICH guidelines developed (ICH Q8, 9, 10) in order to facilitate the implementation of Quality by Design in pharmaceutical industry on a global level [15, 16].
It is reasonable to expect development of similar initiatives between regulatory agencies in the future, including those in area of advanced therapy medicinal products (ATMPs).
17.5 Our Own Experience in Manufacturing and Use of Human Placenta-Derived Mesenchymal Stromal Cells in Phase 1 Clinical Trials Conducted in Australia
17.5.1 Manufacturing Human Placenta-Derived MSC for Clinical Trials
Human mesenchymal stem cells (MSC) derived from a number of different organs and tissues, such as placenta, are increasingly being used in clinical trials for a range of regenerative and inflammatory diseases. At the Mater Mother’s Hospital, Brisbane, there are approximately 10,000 deliveries/year, making term placenta an attractive and readily available tissue for the isolation and manufacturing of clinical grade MSC. Placentas are normally disposed of after delivery, are obtained without invasive procedures, and their use does not elicit ethical debate. Placental MSC (hpMSC) show a classical MSC cell surface phenotype and mesodermal differentiation properties as well as potent immunosuppressive properties [17, 18].
We have been unable to find major differences between hpMSC and human bone marrow MSC (bmMSC) in terms of morphology (Fig. 17.1), cell surface phenotype [19], chemokine receptor display [20], mesodermal differentiation capacity [19] or immunosuppressive capacity [21]. Yen and colleagues [22] found hpMSC to express the embryonic antigens SSEA4, Tra1-60 and Tra1-81, whereas bmMSC did not. However, we found only low level expression of SSEA4 and Tra1-60 on the hpMSC generated from our placental samples [20].
Due to concerns about the sterility of tissue at the time of collection, the placenta is obtained from healthy mothers undergoing elective Caesarean sections as they are performed in a relatively sterile environment. Full informed consent is obtained prior to delivery. The placenta is subsequently double bagged, placed in a cool box and transferred to our manufacturing facility for processing.
Our protocol for the isolation of hpMSC from term placenta utilises a collagenase (GMP grade)-based digestion of tissue which has been dissected and washed to remove blood before isolation of cells. After digestion, large particulate matter is removed by low speed centrifugation and cell suspensions are collected and filtered into fresh tubes using 70 μm filters. The cells are then pelleted by centrifugation, resuspended and erythrocytes are subjected to rapid lysis with water. The cells are washed with Hank’s Balanced Salt Solution (HBSS) and the final cell pellet is resuspended in low glucose-containing Dulbecco’s Modified Eagle Medium (DMEM-LG), 25% foetal calf serum (FCS) and 50 μg/ml gentamycin. Cells are initially seeded into eight T175 (175 cm2) tissue culture flasks and cultured in a humidified incubator at 37°C, 5% CO2 [23]. A scheme of the production schedule is shown in Fig. 17.2.
We used part (300–500 g) of one placenta for each of our first two production manufacturing runs (Fig. 17.3). This represented over 50% of the total mass of the placenta and was used to seed 6× T175 flasks (termed passage 0). This protocol yielded approximately 40 × 106 cells at the first passage, which were then split between 90 flasks at 4.38 × 105 cells/flask (2.5 × 103 cells/cm2). The average yield for each subsequent passage was 7.42 × 108 cells (standard deviation of 8.26 × 107). At each passage, 4.0 × 107 cells were held back for the next passage and used to seed a further 90 flasks at 4.38 × 105 cells/T175 (Fig. 17.4) the remaining cells were cryopreserved.
The cell yields and proliferation rates at each passage were generally consistent, as follows (due to leucocyte contamination proliferation rate was not calculated at passages 0 and 1):
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Placenta 1.
Cell yield (×106): 95(P0), 63(P1), 1160(P2), 400(P3), 960(P4) and 640(P5).
Population doublings: –(P0), –(P1), 4.9(P2), 3.3(P3), 4.6(P4) and 4.0(P5).
Doubling rate per day: –(P0), –(P1), 0.8(P2), 0.6(P3), 0.8(P4) and 0.7(P5).
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Placenta 2.
Cell yield (×106): 562(P0), 38(P1), 760(P2), 720(P3), 631(P4) and 637(P5).
Population doublings: –(P0), –(P1), 4.3(P2), 4.2(P3), 4.0(P4) and 4.0(P5).
Doubling rate per day: –(P0), –(P1), 0.7(P2), 0.7(P3), 0.7(P4) and 0.7(P5).
Release criteria (Fig. 17.5) for cryopreservation were fulfilled: 14 days microbiology culture in passages P0–P5 (sterile); viability >70% by Trypan Blue exclusion; purity by flow cytometry (required to be >85% CD73+, >85% CD105+, <1% CD45+) was as follows: P2: 0.4% CD45, 95% CD73/CD105; P3: 0.0% CD45, 99%CD73/CD105; P4: 0.0% CD45, 91% CD73/CD105; and P5: 0.0% CD45, 96% CD73/CD105; karyotype (P2–P5: cytogenetic analysis normal); Gram stain (P2–P5: negative); mycoplasma test of final product (P2–P5: negative); endotoxin test of final product (P2–P5: <2 EU/ml); pre-donation screening and day 180 donor serology for infectious disease markers (both negative); and pre-donation health questionnaire for mother and day 180 health questionnaire for mother and the baby (both clear).
Although cell recoveries were generally excellent, it was noted that cell recovery at passages 4 and 5 of placenta 1 was only 60%. These cells were still acceptable as they did not fall below our trypan blue-determined viability threshold of 70%. Some of this variability may have been due to the fact that only small aliquots of cells are stored separately (in cryovials) for counting purposes. In our experience, the yield from cryovials is generally slightly lower than for bags. However, viability as determined by trypan blue is generally equivalent.
Sterility testing and cell recovery criteria from the pilot vials for placenta 1-derived hpMSC thawed for infusion into the first patient in our phase I trial of hpMSC were fulfilled at the clinical site testing: sterility 5-day culture (no growth) and cell recovery from pilot vial 96% (P2), 100%(P3), 60%(P4) and 60%(P5), respectively.
17.5.2 Conducting Clinical Trials with Human Placenta-Derived MSC
The Biological Framework was established by the Australian Therapeutic Goods Administrations (TGA) to improve the regulation of human tissue and cellular therapies and provides improved clarity by applying different levels of pre-market regulation to biological products based on the risks associated with the use of each product (TGA 2011). Human placenta-derived mesenchymal stromal cells (hpMSC) are categorised as Class 3 products within the new framework (http://www.tga.gov.au/ct/index.htm#med). As a result, any trial utilising Class 3 hpMSC can be conducted under the TGA’s Clinical Trial Notification (CTN) Scheme. The CTN scheme is designed to combine rapid approval of clinical trial protocols with ongoing monitoring and supervision by HRECs acting in accordance with nationally agreed guidelines developed by the NHMRC (TGA 2004). It is important to note that the TGA does not review any data relating to the trial under this scheme. The Human Research Ethics Committee (HREC) reviewing a new clinical trial protocol utilising hpMSCs must have sufficient experience amongst its committee members in order to effectively review the protocol ensuring scientific validity, and that participant’s rights and well-being are protected according to the Australian National Health and Medical Research Council’s (NHMRC) National Statement on Ethical Conduct in Human Research 2007, the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice ICH GCP(CPMCP/ICH/135/95).
Along with the study protocol, a Participant Information Sheet and Consent Form (PISCF) and other supporting documents including an Investigators Brochure is submitted for review by the HREC and the TGA, and is used by study personnel to facilitate their understanding of the key features of the protocol, in particular, the dosing and methods of administration of the hpMSCs.
In 2007, for our first phase 1 clinical trial, CT4-MSC-UCB-001, a phase I multicentre open label dose-escalation study of unrelated, MHC-unmatched placenta-derived mesenchymal stromal cells (MSC) in recipients of unrelated umbilical cord blood haematopoietic stem cell (HSC) transplants, the total time from submission of the application until approval was received by the HRECs at the Mater Health Services (MHS), Westmead Hospital (Sydney Western Area Health Service) and the Sydney Children’s Hospital (Sydney South Eastern Area Health Service) was 1 year in total. During this time, a request was made by the MHS HREC for an external audit to be conducted on the manufacturing processes outlined in the study protocol which was conducted by staff from the Australian Red Cross Blood Service (ARCBS). Two-way clinical trial agreements were put in place whereby MHS indemnified each of the participating sites for any adverse events related to the administration of the hpMSCs.
One patient was enrolled in this study who later died from pneumonitis related to CMV reactivity [18]. It is important to note that the donor of the hpMSCs was CMV negative prior to the collection of the placenta and again at the follow-up screening period. This study is now closed at all sites, as umbilical cord blood transplants are no longer performed in adults at Westmead Hospital and no recruitment occurred at Sydney Children’s Hospital.CT4 may not have yielded significant clinical results; however, it did highlight some of the impracticalities in incorporating the manufacturing protocol within a clinical trial protocol. As a result, MMRI# CM1: A protocol for manufacturing a human placenta-derived mesenchymal stromal cell bank for use in Mater Health Services Human Research Ethics Committee (HREC)-approved clinical trials was established in 2009. This manufacturing protocol allowed us to continue manufacturing hpMSCs independent of a clinical trial and therefore establish a master bank of hpMSCs. This type of protocol was new to the MHS HREC. After careful consideration, the protocol was approved under the provision that any clinical trial utilising the hpMSCs as the investigational product was to be reviewed by the MHS HREC.
All the hpMSC donors are subject to screening requirements as per the AusCord (Australian National Network of Umbilical Cord Blood Banks and Cord Blood Collection Centres) Guide to Selection of Mothers and Cord Blood Donors. Prior to the collection of the placenta, the donating mother undergoes screening serology for infectious disease markers and completes an in-depth medical questionnaire (as per AusCord Guidelines). The same process is repeated at 180 days after placental donation and information is sought about the health of the baby to identify if any medical conditions have been identified that may exclude the donated placenta.
Upon establishing the master bank of hpMSCs (CM1), respiratory physicians at The Prince Charles Hospital (TPCH) in Brisbane collaborated with our team to submit a clinical trial protocol entitled MSC IPF: A phase 1 study to evaluate the potential role of mesenchymal stromal cells in the treatment of idiopathic pulmonary fibrosis. This study first received HREC approval in September 2009 from the TPCH HREC; however, the clinical trial agreement and research governance aspects were not agreed to until October 2010, more than a year later due to the fact that two completely separate health-care providers were involved—Mater Health Services and Queensland Health. Thus far, 2 patients have received hpMSCs generated by our laboratories with no related adverse events. The novel concept of using hpMSCs in different clinical applications is slowly transferring into the norm. Our most recent clinical trial protocol MSC TEN: A phase 1 trial to evaluate the potential role of MSC in the treatment of chronic refractory tendinopathy only took 4 months to approve. This study is now open for recruitment for patients with chronic refractory Achilles tendinopathy.
ClinicalTrails.gov search listed a total of 192 MSC clinical studies worldwide, including 171 studies with known status (i.e. updated on a regular basis); four clinical trials using bone marrow-derived MSC (bmMSC) are completed or in progress in Australia (Table 17.2), while we currently conduct three clinical trials with human placenta-derived MSC (hpMSC) (Table 17.3).
17.6 Information Required in Applications for Clinical Trials and ICH GCP
In the last 5–10 years much has happened internationally in clinical trials regulation and this is having a direct impact on clinical trial operations on a regional level as well as worldwide.
Different activities including the 2004 agreement between Australia and New Zealand to establish a joint therapeutic goods regulatory agency (which was subsequently postponed), the May 2004 EU Directive implemented in a majority of member states, the April 2004 Japanese merging of three organisations into a single body called Pharmaceutical and Medical Devices Agency (PMDA), many activities in India as it revamps its regulations to make it more attractive for clinical trials, a number of Central and Eastern European countries looking at their new EU member status or non-member status perspectives, and many others, require sponsoring organisations from the developed world to constantly review their strategies and procedures.
However, there is some common practice to pursue, and the majority of regulatory bodies of developed world countries require sponsors to provide most of (or all) the listed information below when submitting an application. To begin any kind of testing on humans, applicant/s must submit the following:
-
Ethical Approval [either by an organisational Human Research Ethics Committee (HREC), Institutional Review Board (IRB) or any other Competent Authority/Ethics Committee].
-
Clinical Trial Protocol and applicable Amendments (if any).
-
Clinical Trial Administrative Details and Clinical Trial Agreements.
-
Introductory Statement and General Investigational Plan.
-
Detailed Information on the investigational drug—chemical, pharmaceutical and biological documentation (chemical formula, method of synthesis and substantiation of its structure, quality specifications for the active compound, if any excipients, information regarding manufacture of the clinical dosage, stability data, suitability for the use proposed); pharmaco-toxicological documentation (preclinical efficacy, toxicology, pharmacokinetic and pharmacodynamic data); previous clinical experience/human experience with that particular investigational drug (if any); any severe adverse events (if applicable).
All above mentioned data may be part of the Investigator Brochure (as required by the FDA and TGA) or separate documents.
-
Detailed Information on Principal Investigator and Clinical Trial Staff.
-
Detailed Information on Laboratories and/or other Facilities to be used.
-
Financial Disclosure (for Medical Staff) and Indemnity Documents may be required at a later stage, but not necessary for the initial application process.
Finally, according to the ICH, GCP is defined as an international, ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected. It is consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible [6].
However, these guidelines may be overridden by national legal requirements and by the requirements of individual regulatory agencies as appropriate, to address matters relevant to local conditions or cultures.
17.6.1 Australia
The Therapeutic Goods Administration (TGA) has adopted the International Conference on Harmonisation (ICH) in principle, to replace the Guidelines for Good Clinical Research Practice (GCRP), but at the same time has recognised that some elements are, by necessity, overridden by the National Statement on Ethical Conduct in Human Research (and therefore not adopted), and that others require explanation in terms of “local regulatory requirements” (see: Notes for Guidance on Good Clinical Practice [CPMP/ICH/135/95]) [7].
The objective of the ICH GCP guideline is to provide a unified standard for the European Union (EU), Japan and the USA to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions. The ICH GCP guideline was developed within the Expert Working Group (Efficacy) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. This guideline was developed after consideration of the codes of good clinical practice of the jurisdictions of the EU, Japan and the USA, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO), in consultation with the relevant government regulatory authorities, in accordance with the ICH process. Generally, it is mandatory that the ICH GCP guideline is followed when generating clinical trial data that are intended to be submitted to regulatory authorities in the developed world.
Approval and authority to conduct clinical trials, such as a first-in-man phase I clinical trial, in Australia rests ultimately with the Secretary of the Federal Department of Health. The approval for this is granted by the Therapeutic Goods Administration (TGA) following successful application process (1). Clinical trials conducted in Australia (of any phase) may be performed under two separate but interrelated programs—known as the Clinical Trials Exemption (CTX) or Clinical Trials Notification (CTN) schemes (1). The difference between CTN and CTX is the level of involvement of the TGA in reviewing data about the therapeutic good involved in the trial before the trial begins (2).
In general, the following information is required:
-
Part 1: Administrative information about the sponsor and a brief overview of the application.
-
Part 2: Chemical, pharmaceutical and biological documentation.
Information in this section includes the chemical formula of the investigational drug and its method of synthesis and substantiation of its structure. Quality specifications must be provided, as well as information regarding the manufacture of the clinical dosage.
-
Part 3: Pharmaco-toxicological documentation.
Preclinical efficacy, toxicology and pharmacokinetic information (particularly data showing the preclinical toxicity testing that was performed and how this relates to the clinical trial proposed). Pharmacokinetic and pharmacodynamic data must also be presented to assure the TGA of the safety of the trial.
-
Part 4: Clinical documentation.
Information detailing any previous clinical experience with the drug in question (if available).
-
Part 5: Documentation of fatal or life-threatening adverse events.
This information is not usually available for drugs in Phase I clinical trial. However, if there is previous clinical experience with the compound, any severe adverse events must be detailed
-
Part 6: Summary information for human research ethics committees (HREC).
Section designed to assist the HREC in their consideration. The TGA also reviews this information to ensure that the HREC is being supplied with relevant data to allow an informed decision-making process to occur with the following documentation generally contained in this section: Summary statement, Status of the medicine in overseas countries, Overview of Chemical, pharmaceutical and biological documentation (Summary of Part 2), Overview of Pharmaco-toxicological documentation (Summary of Part 3), Clinical documentation (Summary of Parts 4 and 5), and Usage guidelines.
17.6.2 USA
Unlike the Australian system of agency approval through the CTX and HREC approval through a CTN, all clinical trial applications in the USA are considered by the FDA. The American system does not allow an HREC to approve a clinical trial, as can occur under the Australian system. In comparison with Australian TGA requirements, the following information is required by the FDA as the USA authority:
-
1.
A cover sheet with administrative information about the sponsor.
-
2.
An introductory statement and general investigational plan.
A brief overview of the objectives of the proposed study and how it fits into the broader development plan for the investigational drug.
-
3.
Investigator brochure.
The Investigator Brochure (IB) is a compendium of all the scientific and clinical data collected to date on the investigational drug and is used by the principal clinical investigators as their primary reference source.
-
4.
Clinical protocol.
-
5.
Chemistry, manufacturing and control information (CMC)
The requirements of this section are essentially identical to those of an Australian regulatory submission. The FDA, like the TGA, recognises that limited information on the manufacturing process, formulation and stability of the investigational drug product may be available early in its development. Information required in this section includes a description of the investigational drug; where and how it is manufactured; quality control limits on its manufacture and its stability, and the manufacture of the clinical dosage form. Additional information (not required in Australian applications) is the requirement to show how the investigational drug (and any placebos) is to be labelled
-
6.
Pharmacology and toxicology information
The format and content of information in this section is very similar to one in the Australian application. A brief overview of the biological and pharmacological properties of the investigational drug is required in addition to summary of the toxicological information collected to date. The summary should contain: brief information about the design and execution of the individual toxicology studies, information discussing how the toxicological information collected in animals relates to and influences the design of the clinical trial and what (if any) pointers it gives to potential human toxicity
-
7.
Previous human experience with the investigational drug.
The application contains information regarding previous clinical experience with the investigational drug, including tabulations of any adverse reactions observed.
The application contains information regarding previous clinical experience with the investigational drug, including tabulations of any adverse reactions observed.
17.6.3 European Union
After more than 10 years of discussions about the need and content of a harmonised approach to clinical trials in Europe (“Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use”), the “GCP-Directive”, finally came into force on April 4, 2001. For several aspects the Directive referred to guidelines which were to be released before May 1, 2003. At this date, the Member States had to adapt and publish the laws, regulations and administrative provisions necessary to comply with the Directive which came into force on May 1, 2004.
The GCP-Directive applies to all Phase I to IV trials intended to discover or verify clinical, pharmacokinetic or dynamic effects of investigational medicinal products and/or to identify any adverse reactions. Non-commercial trials with marketed drugs are covered by the Directive as well. They only can benefit from simplified drug manufacturing requirements, if they deal with indications covered by the marketing authorisation. The Directive does not apply to non-interventional trials.
In March 2010 the European Commission issued a communication “Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial” (2010/C 82/01). This document refers to the Directive 2001/20 and brings clarification of clinical trials authorisation and the type of information required in Member States as well as the “ICH Countries”.
In addition, all Member States regulatory authorities’ requirements apply to clinical trials conducted on their territory.
17.6.4 United Kingdom: How Has the UK System of Drug Regulation Been Affected by Its Membership of the European Union?
The main aim of the EU Directive on Clinical Trails, Directive 2001/20/EC (the Directive) was to simplify and harmonise administrative provisions governing clinical trials across the European Union. The aim was also to provide an environment for conducting clinical research that protects participants without obstructing the discovery of new essential medicines. It applied equally to all commercial and non-commercial trials. Although it was generally considered as a positive development, there were some frustrations expressed in terms of trying to keep up to date with the latest publications and the status at both national and pan-European levels. The UK regulatory framework is implemented through the Medicines and Healthcare Products Regulatory Agency (MHRA). The EU regulations that came into force on 1 May 2004 introduced new procedures for the authorisation of clinical trials (Clinical Trials Authorization, CTA) by MHRA. These new Regulations only applied to trials of medicinal products. Clinical studies involving medical devices, food supplements or other non-medicinal therapies (such as surgical interventions) were not covered by the Directive.
The new regulations have not changed the civil liabilities of the NHS, of universities, or of medical funding bodies in the UK. However, it changed the whole aspect of planned and ongoing clinical trials since it was illegal to start a clinical trial of a medicinal product even if MHRA has issued the authorisation and ethics committee has given a favourable opinion. It was necessary to have a sponsor (either recognised in the EU or with a legal representative recognised in the EU). Many people wanted one general body to take overall responsibility for publicly funded clinical research in the UK, but it was not the case. The Directive specified that it was without prejudice to the civil and criminal liability of the sponsor and of the investigator. Although the proposed Regulation did not change the civil liabilities of NHS, universities or others undertaking clinical trials under the legislation, there were certain changes to reduce the risk of unauthorised clinical research resulting in unexpected liabilities.
One of the requirements of the Directive was that all drug trials are to be conducted according to Good Clinical Practice (GCP). DDXs (Doctors and Dentists Exemptions) and other exemption schemes were not valid from 1 May 2004. If such an exemption certificate was held and the study proceeded beyond April 2004, it required application for a CTA certificate (approval) from MHRA. Approval of the institutional ethics committee was not sufficient any more. The MHRA introduced a waiver system whereby DDXs, CTXs, CTCs and CTMPs could be rolled-over to a CTA. DDXs were specific to a medicinal product whereas CTAs are specific to a trial and the Investigational Medicinal Products (IMPs) used in it.
Under the UK Regulations, investigational medicinal products now need to be supplied and packaged according to Good Manufacturing Practice (GMP), reducing the risk of product liability. The EU Directive and the new UK Regulations clarified specific legal duties of sponsors, investigators and others in clinical trials of medicines (including the national body, MHRA), based on internationally recognised principles. These brought the conduct of clinical trials in the UK much more in line with the USA, since it changed the UK two-tiered system (similar to the Australian CTX/CTN schemes) as mentioned above.
Although a significant amount of information was available, the new legislation caused concerns and it was not always easy to interpret. It was a useful reminder of the need for implementing high standards in clinical research governance—to protect individuals and ensure reliable findings. After already existing criticism on the UK regulatory framework, one may expect further changes in the UK regulatory framework. These criticisms included the fact that virtually all research on drugs and up to 70% of trials reported in major medical journals were funded by the pharmaceutical industry; biases in a way that trial results are interpreted and reported; lack of transparency that the MHRA was legally bound to abide by; lack of public profile and impact; lack of consumer input and serious adverse events in a Phase 1 Healthy Volunteer Clinical Trial conducted in the UK several years ago.
17.7 Comparison of Regional Drug Regulations and Clinical Trial Approval Process
In comparison of the Australian, British and American systems of clinical trials approval, the American system for clinical trials approval has some similarity to the Australian, but also some obvious exceptions (related to CTX/CTN schemes). Until the 1 May 2004 the UK system was basically the same as the one in Australia, with a two-tiered approach. One of the requirements of the EU Directive was that all drug trials are to be conducted according to Good Clinical Practice (GCP) and DDXs (Doctors and Dentists Exemptions) and other exemption schemes were not valid beyond 1 May 2004.
After implementation of EU Directive (Directive 2001/20/EC) in the UK, the regulatory system placed new responsibilities on the sponsor, investigator, and even the regulatory body (such as MHRA). This has brought conduct of clinical trials more in line with the US model. In addition, it required the sponsoring organisation (sponsor) to be a recognised legal entity in the EU or to have an EU recognised legal representative. In terms of Investigational Medicinal Products (IMP), the new system requires production of IMP and the placebos in licenced facilities and in compliance with the Code of Good Manufacturing Practice (GMP). The Code requires that the manufacturer of IMPs hold a current Manufacturer’s Authorisation, and a key requirement for that is that the holder of the authorisation is a Qualified Person (QP). The European Directive goes further and requires that QPs are suitably trained and registered by the appropriate regulatory agency in each EU member state. The QP is required to take considerable personal responsibility for the quality aspects of IMP.
Due to their differences in structure, functional units and scope there are significant differences between the EMA and the FDA. The differences in the review style may be summarised as follows:
-
EMA is an administrative framework, and National Agencies are the scientific reviewers—differences in culture and medical practices, FDA reviewers are within the same Agency.
-
EMA’s organisational and review structure is top-down, while in the FDA is bottom-up.
-
EMA reviewers look into overall benefit/risk projected on the entire data, while the FDA reviewers are more specific (i.e. requires adequate and well-controlled studies).
-
Same data package to both authorities may not necessarily result in the same outcome.
In comparison between US/UK current requirements and the Australian two-tiered clinical trial model is presented by the CTN and CTX schemes. CTN is a notification scheme that enables all material relating to the proposed trial, including the clinical trial protocol to be submitted directly to the HREC. The HREC is responsible for assessing the scientific validity of the trial design, the safety and efficacy, the ethical acceptability of the trial process and approval of the trial protocol. CTN trials cannot commence until a notification letter is sent to the TGA. However, it can commence without any approval given by the TGA. In terms of CTX application (equivalent to IND) another difference is related to the Investigator Brochure (IB) that an IND requires with each clinical trial application, but the current TGA set up does not specifically require this. The IB is a compendium of scientific and clinical data and can be submitted with either the CTX or the CTN scheme, although is not an absolute requirement. The TGA requires the sponsor to be an Australian entity [individual (e.g. a medical practitioner), a body or organisation (i.e. a hospital, non-government organisation), or a company (i.e. a pharmaceutical company)]. In the American system, the FDA accepts foreign clinical studies (not conducted under an IND) if they comply with specific requirements (i.e. provided they are well designed, performed by qualified investigators, and conducted in accordance with ethical principles acceptable to the world community as stated in “Declaration of Helsinki”). Generally speaking, the previous situation (prior to 1 May 2004) was quite attractive for pharmaceutical companies so they have moved a number of early phase clinical trials programs from the USA to Britain, Europe and Australia. In terms of already implemented changes in EU countries, the Commonwealth Department of Health has been carrying out a review of Australian clinical trials system. It is reasonable to expect further harmonisation and discontinuation of the existing differences.
17.8 Conclusions
Paradigms arising from drug regulatory frameworks and their inevitable harmonisation can be applied to biological therapeutics regulations. Use of a shared approach in early clinical trials might reduce time and resources for new drugs (including new cell drugs) to reach late-stage clinical trials. This may increase collaborative efforts across the globe and enhance chances of new biologic drugs reaching the market. To date, this has been a long and painful process, led by major industry players with significant funding.
Regulatory frameworks established by national agencies should provide stable, structured and reliable but not overly restrictive support. Advancing the regulatory framework’s harmonisation process will eventually increase the likelihood of biomedical discoveries for millions of neurological, cardiovascular, oncology, haematology, reconstructive surgery, paediatric oncology and other patients.
Phase I clinical trials are proven to be the most challenging step in this process due to limited funding, laborious and long manufacturing procedures and the need for a multi-disciplinary team with a unique skill set.
Manufacturing of human placenta-derived hpMSC for phase I clinical trials, expected to assess safety of product, is a complex process. Adherence to the Code of Good Manufacturing principles and Quality Management System principles has become mandatory from the regulator’s perspective and from the patient and staff safety perspective. Further trials of placenta-derived MSC are underway at our centre.
Thoroughly planned and safely conducted clinical trials in accordance with ethical principles and with adherence to rigorous regulatory requirements are needed to advance the field and provide valid clinical research data. The “open system” of manufacture is labour-intensive and to move to large multi-centre trials a large scale closed bioreactor system compliant with GMP will be required. We are currently pursuing this technology.
Abbreviations
- ARTG:
-
Australian Register of Therapeutic Goods
- CBER:
-
Center for Biologics Evaluation and Research
- CDER:
-
Center for Drugs Evaluation and Research
- CFR:
-
Code of Federal Regulation
- CTN:
-
Clinical Trial Notification
- CTX:
-
Clinical Trial Exemption
- DDXs:
-
Doctors and Dentists Exemptions
- EMA:
-
European Medicines Agency
- FDA:
-
Food and Drug Administration
- GCP:
-
Good Clinical Practice
- GMP:
-
Good Manufacturing Practice
- HREC:
-
Human Research Ethics Committee
- ICH:
-
International Conference on Harmonisation
- IND:
-
Investigational New Drug Application
- IRB:
-
Institutional Review Board
- MHRA:
-
Medicines and Healthcare Products Regulatory Agency
- PMDA:
-
Pharmaceutical and Medical Devices Agency
- TGA:
-
Therapeutics Goods Administration
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Acknowledgments
The authors would like to acknowledge funding from the Inner Wheel Australia, Mater Foundation, Therapeutic Innovation Australia (formerly Research Infrastructure Support Services), The Australian Stem Cell Foundation and Mater Health Services for making this work possible.
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Ilic, N., Khalil, D., Hancock, S., Atkinson, K. (2013). Regulatory Considerations Applicable to Manufacturing of Human Placenta-Derived Mesenchymal Stromal Cells (MSC) Used in Clinical Trials in Australia and Comparison to USA and European Regulatory Frameworks. In: Chase, L., Vemuri, M. (eds) Mesenchymal Stem Cell Therapy. Stem Cell Biology and Regenerative Medicine. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-200-1_17
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DOI: https://doi.org/10.1007/978-1-62703-200-1_17
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