Manufacture and Regulation of Cell, Gene, and Tissue Therapies: Part 2 — Regulatory Guidances

19-4-FR-Apte-Part2-P1-300x258.jpgThe US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Medicines and Healthcare Products Regulatory Agency (MHRA), and Japan’s Pharmaceutical and Medical Devices Agency (PMDA) all offer support and guidance for developers of advanced therapy medicinal products (ATMPs). Some agencies have issued guidelines to help companies through different stages of product development — from research and development to marketing authorization and postauthorization activities. Such guidelines are updated regularly as more knowledge becomes available from the development and approval of new ATMPs. For example, the EMA guidelines now have draft guidance for investigational medicinal products and for authorized products (1), and the FDA has issued guidelines on the development of gene therapy products (2).

Regardless of the region, regulators expect ATMP developers to comply with current legislation on good manufacturing practices (GMPs), good clinical practices (GCPs), and good laboratory practices (GLPs), with some flexibility permitted according to the developmental stage of their products. Because more ATMPs are targeted toward diseases with high unmet medical needs, and because small- and medium-sized companies and academia typically pioneer those products, regulatory agencies also provide expedited pathways and incentives to bring such medicines to patients. Although the agencies differ in their modes of operation, their shared objective is to ensure that patients receive products of the highest possible quality, efficacy, and safety.

In part one of this article (3), we covered the chemistry, manufacturing, and controls (CMC) challenges of manufacturing ATMPs. Below, we highlight the role of different regulatory agencies and the support they provide to ATMP developers.

Role of the EMA
The EMA authorizes all ATMPs through a centralized procedure. It allows marketing authorization holders (MAHs) to market such drug products in all countries of the European Union (EU) through a single marketing authorization. So ATMP developers benefit from a single validation, scientific evaluation, and approval process. The EMA also monitors the safety and efficacy of such medicines postapproval and provides support for the design of pharmacovigilance and risk management systems (4, 5).

Efficient evaluation of ATMPs involves the Committee for Advanced Therapies (CAT), Committee for Medicinal Products for Human Use (CHMP), Committee of Orphan Medicinal Products (COMP), Paediatric Committee (PDCO), and other working parties within the EMA, including national competent authorities (NCA) of different member states (MSs) of the European Union (EU) as part of the EMA committees (4, 5).

Although marketing authorization takes place through the centralized procedure, clinical trial authorization (CTA) applications are approved at the national level through NCAs of the MSs and their ethics committees (EC) — independent departments of the EU to which a CTA is submitted. If ATMP classification is ambiguous, the EMA advises sponsors to apply for ATMP classification to determine whether a product meets the criteria set for ATMPs.

EMA Orphan Medicinal Products Designation

The EMA designates an ATMP as an orphan medicinal product if the product meets the criteria listed below.

It must be intended for the treatment, prevention, or diagnosis of a disease that is life-threatening or chronically debilitating.

The prevalence of the condition in the EU must not be more than five in 10,000, or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development.

No satisfactory method of diagnosis, prevention, or treatment of the condition concerned can be authorized, or if such a method exists, the medicine must be of significant benefit to those affected by the condition.

EMA Support and Incentives: Innovation Task Force (ITF) Meetings: Sponsors can use ITF meetings to have informal dialogue with the EMA to understand the marketing route and to keep informed about current developments. Both ATMP classification procedure and ITF meetings are free of agency fees.

Priority Medicine (PRIME) Designation: Sponsors can apply for PRIME designation of medicines targeting highly unmet medical needs and/or offering significant therapeutic innovation. Because small and medium-sized enterprises receive regulatory, financial, and administrative assistance (along with other incentives), they must apply for small or medium-sized enterprise (SME) status (6). If granted, SME status expires two years after the date of closure of the accounts on which the declaration was based. To renew SME status, an enterprise must provide the required documentation and application form to the EMA (6).

Scientific advice (SA) is formal advice provided by the EMA based on questions posed by a sponsor to understand whether its development (nonclinical and clinical) programs are appropriate or whether additional studies are necessary to ensure that a marketing authorization application (MAA) will be satisfactory (7). SA is prospective and cannot be considered to be a preevaluation of data for an MAA. A sponsor can obtain SA at any stage of a product’s development. The EMA provides 65% fee reduction for SA for ATMPs, and SMEs receive 90% fee reduction for SA. If a product has been granted orphan designation (described below), then SMEs and academics can claim further reductions. The EMA also can issue qualification advice on protocols and methods for specific use of a novel methodology.

Certification Procedures: SMEs can get quality data and nonclinical data evaluated by the CAT at any stage of product development. This is meant to address potential issues before MAA submission, according to Article 18 of Regulation No. 1394/2007 (8). Unfortunately, no such incentive is possible for academia.

Orphan Medicinal Products Designation: ATMPs also can be classified as orphan medicinal products (9) if they meet all criteria as quoted on the EMA website and in the box above. Developers of orphan products are granted 10 years of market exclusivity, including two years’ exclusivity for a completed pediatric investigation plan (PIP).

Compassionate Use: Patients suffering from a severe life-threatening condition and for whom no other suitable treatment is available can benefit from medicines that have not been authorized but have gone through clinical trials. Such patients, who for any reason have been unable to enter a clinical trial, thus can receive these medications through “compassionate use.” Because such rules might differ among MSs, the national framework needs to be checked.

Hospital Exemption Scheme: In the European Union, ATMPs must be approved through the centralized procedure. However, ATMPs developed on a nonroutine basis or personalized for patients (not meant for commercial development) can be administered exclusively by a medical practitioner within the individual MS under the hospital exemption scheme. Again, details differ according to each MS, and a drug product can be administered to a patient only in the MS in which that product is manufactured.

Role of the Medicines and Healthcare Products Regulatory Agency (MHRA)
With ongoing Brexit discussions and the MHRA leaving the European Union, we must include here the support available for ATMP developers in the United Kingdom. The MHRA has established an innovation office (10) as a single point of contact to offer free regulatory advice and guidance to all companies involved in innovative medicines that do not fit the normal regulatory framework. Expert advice is available from specialists across the MHRA, the Clinical Practice Research Datalink (CPRD), and the National Institute for Biological Standards and Controls (NIBSC). Once a query is submitted to the innovation office, a single consolidated document is provided that contains regulatory information and advice, usually within 20 days, depending on the complexity. A regulatory advice meeting can take place if the innovation office deems that to be necessary.

The innovation office also has established a regulatory advice service to address queries specific to regenerative medicines. A single document is provided with advice from the Health Research Authority (HRA), Human Fertilization and Embryology Authority (HFEA), Human Tissue Authority (HTA), National Institute for Health and Care Excellence (NICE), and specialists across the MHRA, CPRD, and NIBSC. If necessary, advice also can be obtained from the Health and Safety Executive (HSE) and Department for Environment, Food, and Rural Affairs (DEFRA).

Promising Innovative Medicine (PIM) and Early Access to Medicines (EAMS): EAMS is an MHRA incentive for innovative medicines targeting clear unmet medical needs (11). Patients suffering from life-threatening serious conditions can get early access to medicines that have not yet obtained market authorization. MHRA provides a scientific opinion for a medicine after a two-step evaluation: PIM designation and early access to a medicine scientific opinion. The EAMS scheme is connected to a patient registry that needs to be agreed upon with the MHRA.

Role of the FDA
The Office of Tissue and Advanced Therapies (OTAT) at the Center for Biologics Evaluation and Research (CBER) of the FDA regulates cell and gene therapies in the United States. OTAT supports both the Public Health Services (PHS) Act and the Federal Food, Drug, and Cosmetics (FDC) Act. Sponsors must submit investigational new drug (IND) applications to the FDA to conduct clinical trials and submit a biologics license application (BLA) for product marketing (12). For combination drug and medical device products in which the primary mode of action cannot be determined, a request for designation (RFD) can be submitted to the Office of Combination Products (OCP).

The Office of Biotechnology Activities (OBA) and the Recombinant DNA Advisory Committee (RAC) at the National Institutes of Health (NIH) also oversee gene therapy products because most clinical trials are conducted at research institutes where funding is provided to some extent by NIH (13). In such cases, sponsors are required to provide clinical trial protocols to OBA and the Institutional Review Board (IRB) for review. Those protocols also are subject to review by the RAC.

FDA Orphan Drug Designation

The FDA can designate an orphan medicinal product according to both criteria below.

Drugs (including biologics) are for the prevention, diagnosis, or treatment of diseases or conditions affecting fewer than 200,000 people in the United States or more than 200,000 persons but not enough to recover the costs of developing and marketing the drug.

If significant benefit over existing treatments is shown, then the product will receive seven years (compared with five years) market exclusivity as per Orphan Regulations of 21 CFR 316.3 (b) (15).

Support and Incentives: The Orphan Drug Act (ODA) provides for granting special status to a drug or biological product that treats a rare disease or condition upon request of a sponsor (14). This status is referred to as orphan designation (or sometimes orphan status). For a drug to qualify, both the drug and the disease or condition must meet the criteria shown in the “FDA Orphan Drug Designation” box.
Orphan designation qualifies a sponsor for product development incentives of the ODA, including tax credits for qualified clinical testing. A marketing application for a prescription drug product that has received orphan designation is not subject to a prescription drug user fee unless the application includes an indication other than the rare disease or condition for which the drug was designated.

Fast-track designation is granted to an IND with a potential to treat a life-threatening, unmet medical need, as evident from nonclinical and clinical data. If substantial clinical data are available at the time of marketing application submission, then the drug product also can be eligible for priority review.

Breakthrough therapy designation is given to an IND with preliminary clinical data that show a substantial clinical benefit to treating a highly serious illness better than available therapies, based on one or more clinically significant endpoints. Most products that receive this designation are gene therapies.

Regenerative medicine advanced therapy (RMAT) designation is granted to an IND that meets the definition of regenerative medicine therapy (16) as stated by the FDA, with the potential to treat, modify, reverse, and/or cure a serious condition of unmet medical need, based on preliminary clinical evidence. Those data should indicate that the drug can address that unmet need. Different cell and gene therapies targeting unmet medical needs have met the FDA’s RMAT designation.

Priority review designation is given to products — including those that with fast-track, breakthrough-therapy, and/or RMAT designations — that demonstrate enhanced safety or efficacy over current treatments at the time of BLA submission. The appropriate time for sponsors to discuss this designation is before their BLA meeting with CBER.

Accelerated approval is granted for products that offer advantages over current therapies or alternative treatments and that demonstrate a clinical effect on defined surrogate and clinical endpoints other than irreversible morbidity or mortality. RMAT-designated products might be eligible based on an agreed endpoint or on a meaningful number of investigation sites. Designation is comparable to “conditional marketing approval” in the European Union. In addition, pre-IND and end-of-phase 1–3 meetings that typically are provided for small molecules and biologics are available for advanced therapies.

PMDA Orphan Drug Product Criteria

According to the Pharmaceuticals and Medical Devices Agency, orphan products must meet following criteria:

The number of patients is fewer than 50,000 in Japan (2016 population 126.9 million) (17).

Medical Needs:

Possibility of Development: There should be a theoretical rationale for use of the product in treating the target disease, and the development plan should be appropriate.

Role of Japan’s Pharmaceuticals and Medical Devices Agency (PMDA)
In 2014, the PMDA adapted the Act on the Safety of Regenerative Medicine (Safety Act) to include new regulatory pathways and a risk-based classification (17) for regenerative medicines (identified as medicinal products based on human cells, tissues, or genes). Such regenerative medical products (RMPs) are defined as processed (by more than minimal manipulation) live human or animal cells that are intended to be used as gene therapies or for either reconstruction, repair, or formation of structures or functions of the human body; or treatment or prevention of human diseases.

The PMDA is responsible for evaluating clinical trials and marketing authorizations (MAs) in Japan. A number of guidelines also have been issued for RMPs since 2008. (The first guidance on gene therapy was issued in 1995.)

Support and Incentives: All three areas below apply to basic research to clinical research and trials, approval reviews, safety measures, insurance coverage, improvement of infrastructure, and the environment for corporate activities and global expansion.

Conditional and Time-Limited Approval: According to the 2014 Act on Pharmaceuticals and Medical Devices (PMD Act), all clinical trials with RMPs must be authorized through governmental committees. They are submitted for conditional and time-limited approval, which is valid for a maximum of seven years. During that period, pivotal trials are required for a company to achieve a full MA. If data are not provided or do not support the MA, then that MA is withdrawn.

Sakigake Designation System/Priority Review: The Ministry of Health, Labor, and Welfare (MHLW) issued the Sakigake (meaning pioneer) program in 2015 (18). It promotes research and development in Japan, with focus on early practical application for innovative pharmaceutical products, medical devices, and regenerative medicines. The program includes prioritized consultation (corresponding to SA for clinical trials), extensive preapplication consultation before submission (rolling review), and priority review (taking action on an application within six months) with a review PMDA manager.

Orphan drug products must meet criteria described in the “PMDA Orphan Drug” box. The PMDA provides a priority review for orphan drugs.

Take Advantage of Regulatory Support
ATMPs have gained much interest among physicians and patients because of groundbreaking results and the curative nature of these therapies. Developers of such products should take advantage of all existing opportunities to keep abreast of successes and failures in this field to help these companies commercialize their products safely. Upfront development activities and risk-based assessments are critical to reducing CMC risks during and after development. Such efforts along with early involvement with regulators will be keys to success.

1 Guidelines Relevant for Advanced Therapy Medicinal Products. European Medicines Agency: Amsterdam, The Netherlands;

2 Cell and Gene Therapy Guidances. US Food and Drug Administration: Silver Spring, MD;

3 Apte A, et al. Manufacture and Regulation of Cell, Gene, and Tissue Therapies — Part 1: Chemistry, Manufacturing, and Control Challenges. BioProcess Int. 18(11–12) 2020: i6–i12;

4 Advanced Therapy Medicinal Products: Overview. European Medicines Agency: Amsterdam, The Netherlands;

5 Detela G, Lodge A. EU Regulatory Pathways for ATMPs: Standard, Accelerated, and Adaptive Pathways to Marketing Authorisation. Mol. Ther. Methods Clin. Dev. 13, 2019: 205–232;

6 Applying for SME Status. European Medicines Agency: Amsterdam, The Netherlands;

7 Scientific Advice and Protocol Assistance. European Medicines Agency: Amsterdam, The Netherlands;

8 Certification Procedures for Micro-, Small-, and Medium-Sized Enterprises (SMEs). European Medicines Agency: Amsterdam, The Netherlands;

9 Orphan Designation: Overview. European Medicines Agency: Amsterdam, The Netherlands;

10 MHRA Innovation Office. Medicines and Healthcare products Regulatory Agency; London, UK;

11 Apply for the Early Access to Medicines Scheme (EAMS). Medicines and Healthcare Products Regulatory Agency; London, UK;

12 Cellular and Gene Therapy Products. US Food and Drug Administration: Silver Spring, MD;

13 Ramina G. Regulation and Oversight of Gene Therapy in the US. Reg. Focus. Regulatory Affairs Professionals Society: Rockville, MD, 27 February 2017;

14 Designating an Orphan Product: Drugs and Biological Products. US Food and Drug Administration: Silver Spring, MD;

15 Hourd P, et al. Regulatory Challenges for the Manufacture and Scale-Out of Autologous Cell Therapies. StemBook. The Stem Cell Research Community. IOS Press: Amsterdam, The Netherlands;

16 Regenerative Medicine Advanced Therapy Designation. US Food and Drug Administration: Silver Spring, MD;

17 Maruyama Y. Regulation of Regenerative Medicine in Japan. Health Products Regulatory Conference, 18–19 May 2017;

18 Strategy of Sakigake As a Package. Pharmaceuticals and Medical Devices: Tokyo, Japan;

Anjali Apte is manager of regulatory affairs, CMC ([email protected]); Adeyemi Afuwape is associate director of regulatory affairs, CMC ([email protected]); Zaklina Buljovcic is director of scientific services and principal consultant, innovative therapies ([email protected]); and Zeb Younes is director regulatory affairs, CMC ([email protected]), all at PharmaLex.

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