Regulatory Review Pathways (IND to BLA, CTA to MAA) PDF

The Regulatory Review Pathways (IND to BLA; CTA to MAA) Chaya Mazouz May 2024  Drug regulation is the control of drug use by international agreements and/or by regulatory authorities such as the US Food and Drug Administration (FDA)...

The Regulatory Review Pathways (IND to BLA; CTA to MAA) Chaya Mazouz May 2024  Drug regulation is the control of drug use by international agreements and/or by regulatory authorities such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) Drug Regulation (1) Regulations are concerned with the development, approval, manufacturing and marketing of drugs (life cycle) Drug regulators assess the drug's benefit–risk balance, that is, “balancing the desired effects” or benefits of a medicine against its undesired effects or risks 2  Often a challenging and complex task given the extensive body of evidence submitted by the applicant of a New Drug Application (NDA)/Biologics Licensing Application (BLA) or Marketing Authorization Application (MAA) Drug Regulation (2) Additional considerations going beyond the typical measures of a drug's benefits and risks can further complicate the evaluation procedure, including the severity of the condition, the unmet clinical need based on the availability of current therapies, the uncertainty about how available clinical trial data might translate to broader use after approval, and the potential need for risk management tools 3  The goal of the regulatory affairs is human health protection Ensuring safety, efficacy, and quality of drugs, ensuring appropriateness and accuracy of product information The Regulator’ Role The success of regulatory strategy is not only dependent on the regulations, but on how they are interpreted, applied, and communicated within and without companies Regulatory Affairs is involved in all stages of drug development and after drug approval and marketing (life cycle) 4 The European Medicines Agency (EMA) ▪ EMA is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or European Medicines Evaluation Agency (EMEA) ▪ The EMA is responsible for the scientific evaluation of centralized MAA. Once granted by the European Commission (EC), the centralized marketing authorization is valid in all EU member states, Iceland, Norway and Liechtenstein The Food and Drug Administration (FDA) ⁄ FDA is an agency of the United States (US) Department of Health and Human Services, one of the US federal executive departments ⁄ The FDA is responsible for protecting and promoting public health through the regulation and supervision of food safety, tobacco products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED), veterinary products, and cosmetics 6  ▪ Though science remains the fundamental initiative behind a successful new drug application, effective communication between companies and regulatory authorities at each stage of the development Regulatory process stands as an essential element in securing approval for any suggested Pathway therapy ▪ Applicant companies that frequently gain approval and avoid delays, practice not only good science but also cultivate and maintain strong working relationships with the authorities and its personnel Regulatory Pathway Optimizing ▪ There can be many risks in the long and mysterious journey from concept to market…. ▪ Effective communication with regulatory authorities is an investment which can make the difference between smooth driving and a very choppy ride…  The science is the same Documentation requirements are mostly the EMA & FDA same; some minor differences Similarities Most of Module 3 (CMC/quality) can be the same for EMA and FDA Same data package to both agencies may result differently The Development Process EMA Development Process  FDA Development Process Product Manufacturing Development Good Manufacturing Practice (GMP) ▪ Manufacturing in pilot facility ▪ Defining critical parameters ▪ Defining process and product control ▪ Optimizing process steps ▪ Manufacturing at industrial scale ▪ Reliable and repeatable manufacturing process ▪ Product fully characterized, high quality, ensuring product safety and efficacy Pre-Clinical Development Good Laboratory Practice (GLP) ▪ Pharmacology studies: ▪ Pharmacodynamics (PD) ▪ Drug’s action on various receptors of physiological systems ▪ Pharmacokinetics (PK): ▪ Extent and duration of systemic exposure to drug ▪ Safety studies: ▪ Short-term toxicity ▪ Long-term toxicity Clinical Development Good Clinical Practice (GCP) ▪ Phase I studies Healthy subjects ( 550,000 (final/draft, FDA/ICH) 20 EMA – What We Do? Facilitate development Evaluate applications Evaluate applications Monitor the safety of and access to medicines for marketing for marketing medicines across their authorization authorization lifecycle  FDA web site https://www.fda.gov/ http://www.fda.gov EMA web site https://www.ema.europa.eu/en Collecting Freedom of information (FOI) Information Summary basis of approvals, audit reports, warning letters, approval status of different products Direct contact to agencies  Pre-submission correspondence Request to test the investigational product Regulatory Process Application for product approval Marketing authorization 23  Communication with the FDA ▪ Type A: Stalled Development Program ▪ Held Within 30 Days of Receipt ▪ Type B: “Milestone” Meeting (pre-IND, end of Phase 1 or 2, pre- NDA) ▪ Held Within 60 Days of Receipt ▪ Type C: Any Other Request for Advice ▪ Held Within 75 Days of Receipt IND Review Process Pharmacology/Toxicology review 30 days clock review… Chemistry review Clinical review 30 days → no answer → study starts Allows clinical testing to proceed Deficiency letter through its silence Clinical hold 25  ▪ ▪ ▪ ▪ Clinical Hold ▪ ▪ ▪  ▪ Communication ▪ with the EMA Scientific ▪ Advice  ▪ ▪ Communication with the EMA ▪ Protocol Assistance ▪  By the first contact, you have already invested a significant amount of time and funds, therefore you should be prepared Remember, the authorities want you to succeed; they are Meeting the trying to be helpful; however, they are the patients advocate and have a mandate to both protect and Regulators promote public health There are specific standards that must be met to address regulatory concerns, but they are willing to discuss how to successfully address those concerns in order for your product to be tested in the clinic. They Want You to Succeed!! Investigational ▪ Medicinal Product Dossier (IMPD) ▪ Investigational New Drug (IND) (1)  ▪ Investigational Medicinal Product Dossier (IMPD) Investigational New Drug (IND) ▪ (2) Common Technical Document - CTD ▪ ▪ ▪ ▪ ▪ ▪ The CTD  Objectives and rationale of drug/clinical research Indication (s) to be studied Module 1: General approach to be followed in evaluating the drug General Investigational Clinical trials to be conducted in the following year Plan Estimated number of patients Anticipated risk 34 Institutional Review Board (IRB) Administrative body established to protect the 21 CFR 56 rights and welfare of human research subjects recruited to participate in research activities conducted under the auspices of the institution with which it is affiliated  IRB Research institution/hospital/center Centralized IRB (e.g. WIRB) who conduct clinical studies Consists of at least 5 members Qualified through experience and expertise At least one from non-scientific area At least one independent from institution/site May invite experts for assistance (non-voting) Member with conflicting interest may not participate in review/vote 36  ▪ An independent body in a member state of the EU, consisting of healthcare professionals and Ethic non-medical members, whose responsibility is to protect the rights, safety and well being of human Committee (EC) subjects involved in a clinical trial and to provide Directive public assurance of that protection, by, among other things, expressing an opinion on the clinical 2001/20/EC trial protocol, the suitability of the investigators involved in the trial and the adequacy of facilities, and on the methods and documents to be used to inform trial subjects and obtain their informed consent ▪ With the Clinical Trials Directive, the EU envisioned a harmonization of research ethics committees across Europe, including the time taken to assess a trial proposal and the kind of issues a committee should consider IRB/EC; Responsibilities Review and approval of Review and approval of clinical protocols protocol amendments Review and approval Inform Consent; ensures that Reporting and record participants are keeping adequately informed about the clinical study 38  Investigator’s Brochure Clinical protocol / amendments IRB/EC; Informed consent / updates Submission Recruitment procedures Written patient instructions All safety information Financial disclosure information CV of investigator Special IRB forms Others  Must be in writing! IRB/EC; Approval Minimum information ▪ Opinion and approval date ▪ Name and address of IRB/EC ▪ Clear identification of the trial ▪ Documents reviewed (version/date) ▪ What was approved ▪ Investigator’s Name ▪ Modification required Regulatory Strategy Considerations For Working With FDA vs. EMA ▪ As regulatory requirements become increasingly harmonized across the globe, the development and marketing of pharmaceutical products worldwide are also becoming more streamlined ▪ Science is the same, however, global regulations are not one-size-fits-all ▪ Same data package to both may not result in the same outcome  Requirements US (FDA) EUROPE (EMA) Under EU law EMA has no authority to permit marketing in the different EU countries. The EC is the authorizing body for all centrally authorized product, Drug and who takes a legally binding decision based on EMA's biologic approval recommendation. Once granted by the EC, the Governance process in the centralized MAA is valid in all EU Member States as well EU vs.US United States as in the European Economic Area countries Iceland, Liechtenstein and Norway. Regulatory As of January 1, 2021, EU pharmaceutical regulations do not apply to the United Kingdom Oversees all Two main routes for authorizing medicines: a centralized drug approvals in route and a national route Approval Process the US via Some products have specific requirements dictating BLA/NDAs which of these pathways is appropriate  Meetings with Regulatory Agencies: US vs EU (1) ▪ There are two categories of meetings with regulatory authorities with some overlap between the two ▪ Scientific advice meetings ▪ Pre-submission meetings ▪ Scientific advice meetings, the goal is to confirm the adequacy of existing information to support the next steps in a development program. In addition, the sponsor seeks an agency’s agreement on its proposed plans, including clinical and nonclinical studies. ▪ Pre-submission meetings are usually associated with milestone submissions, such as applications to initiate clinical trials or marketing applications. These meetings usually focus on the administrative, regulatory, and technical aspects of a submission, while including discussion of the adequacy of the development program to support the given application. ▪ A sponsor must submit a list of specific questions prior to a meeting with either the US or EU authorities  Requirements US (FDA) EUROPE (EMA) Questions to be Sponsor to provide its position for each discussed with the Only questions question agency Authorship of the Sponsors to compose the minutes and share Meeting minutes to them with the agency. They will then review official record for each serve as an official the minutes, suggest any changes, and issue meeting record confirmation of an official record US vs EU Meetings with Depending on the scope of the advice. Regulatory Agencies Fee None Fees ranged from €44,400 to €89,000), though fee reductions are available for orphan drugs and small businesses the Scientific Advice Working Party (SAWP) reviews request monthly. Letter of intent and briefing package to be Meeting requests and submitted 3 weeks (without a meeting) or ~ On demand 7 weeks (pre-submission meeting). The schedules meetings SAWP reviews the briefing package and decides whether scientific advice can be provided without a meeting, or whether a 90-minute discussion meeting will be held Applications for the Conduct of Clinical Studies (IND) ▪ IND application regulations cover all US clinical activities for drugs and biologics ▪ IND submission serves as a request to start clinical studies, containing a summary of information known about the drug, including nonclinical studies; chemistry, manufacturing and controls (CMC); and a proposed clinical plan ▪ Primary goal of the initial submission is to demonstrate the product’s safety for clinical trial participants and to justify the proposed starting dose in humans ▪ IND is a living dossier that a sponsor submits before the first clinical study and then expands throughout the clinical program for the given indication, with some INDs accruing upwards of 100 amendments  Requirements US (FDA) EUROPE (EMA) Full study Questions to be discussed reports of Upon request by reviewing with the agency nonclinical and authority clinical studies Fees often apply for CTA submissions both to the National Competent Authority (NCA) of each member state and to relevant US vs EU Fee None Independent Ethics Committees Applications for the (IECs), which are equivalent to Institutional Review Boards (IRBs) Conduct of Clinical in the US. Studies (INDs vs CTAs) (1) Covers the entire clinical New CTA must be submitted for Submission procedure program for a each new trial given product and indication  Requirements US (FDA) EUROPE (EMA) New Clinical Trial Regulation introduces a major change to the conduct of clinical trials in the EU. From January 31, 2022, a centralized EU portal and database for clinical US vs EU Study registration Registered at trials, the Clinical Trials Information System (CTIS), is live with the goal of Applications for the clinicaltrials.gov increasing the safety and efficiency of Conduct of Clinical trials and increasing the transparency of information. Notable changes Studies include a single e-submission to all Concerned Member, a joint (INDs vs CTAs) (2) assessment, and the availability of all information related to the clinical trial Updated utilizing Revised over time and must be IND vs. IMPD amendments to the resubmitted with each new CTA initial IND Expedited Programs: Breakthrough Therapy vs PRIME ▪ Several expedited programs/designations exist both in the US and in the EU to aid in the development of medicines for patients with unmet medical needs ▪ Breakthrough Therapy designation is intended for medicines that represent a substantial improvement in safety or effectiveness (as demonstrated by preliminary clinical evidence) over available therapies for the treatment of a serious condition. When the designation is granted, the FDA offers intensive guidance on the drug development program, beginning at phase 1, as well as enhanced interactions involving senior managers. Products with Breakthrough Therapy designation may also benefit from priority review, which shortens the NDA/BLA review time from 10 months to 6 months. Between 2012 and 2020, 190 medicines received Breakthrough Therapy designation. ▪ The PRIME scheme provide increased support for the development of medicines that target an unmet medical need. PRIME offers sponsors enhanced interactions and early communication with the EMA, with the goal of optimizing development and accelerating the evaluation of a product in order to provide benefit to patients as soon as possible. Medicines that offer a major therapeutic benefit over existing therapies or that benefit patients without treatment options are considered for PRIME based on early clinical data. PRIME medicines may also be eligible for accelerated assessment, a counterpart of priority review by the FDA, which reduces the review time of a MAA from 210 days to 150 days. Between 2016 and June 2021, 93 medicines (25% of all applications) were granted PRIME eligibility  ▪ In the US, the Pediatric Research Equity Act (PREA) requires sponsors to conduct pediatric studies of certain drugs or biologics (including an age-appropriate formulation) with the Pediatric goal of obtaining pediatric labeling for the product. PREA Plans: PSPs vs instituted a requirement for pediatric study plans (PSPs), which must be submitted no more than 60 days after an PIPs End of Phase 2 (EOP2) meeting, or at least 210 days prior to NDA submission if no EOP2 meeting is held. The FDA may defer the requirements or grant partial or full waivers of studies in certain age groups based on low or no occurrence of a specific condition in pediatrics ▪ In the EU, pediatric investigation plans (PIPs) are analogous to PSPs; however, the submission timing for a PIP is different. A PIP must be submitted to the EMA after Phase 1 pharmacokinetic studies and before Phase 3 studies. As with the FDA, the EMA may grant partial or full waivers of studies as well as deferrals Labeling: PI vs SmPC ▪ Labeling information for prescription products approved in the US can be found in the Prescribing Information (PI) and accessed in its most up-to-date form at Drugs@FDA. Labeling information for products approved in the EU is located in the Summary of Product Characteristics (SmPC), accessible via the EPAR database. ▪ Craft a time- and cost-efficient development strategy that enables to attain approval in both the US and the EU  ▪ Drug approval processes are designed to allow safe and effective drugs to be marketed ▪ Drug regulatory agencies in various countries attempt to rely on premarketing scientific studies of the effects of drugs in animals and humans in order to determine if new drugs have Drug Approval a favorable risk-to-benefit ratio ▪ Although most countries require similar Process types of premarketing studies to be completed, differences in specific regulations and guidelines exist ▪ Many drug regulatory agencies have attempted to produce harmonization among regulations in various parts of the world. Harmonization, which aims to make regulations and guidelines more uniform Marketing Review Process - FDA NDA/BLA review time < 12 months (~10 months) ▪ Within the review process ▪ Questions related to dossier ▪ Pre-Approval Inspection to manufacturing facility ▪ Usually 6-7 months post-submission. Can also be immediate ▪ Focuses on compliance with cGMP requirements ▪ Pre-Approval Inspection to the clinical sites ▪ Focuses on compliance with GCP requirements ▪ Data integrity  ▪ IND written approval not required to proceed commence Clinical Trials CT Application US ▪ May proceed 30-days after FDA receives IND unless notified otherwise ▪ IND annual report required ▪ Format paper or electronic, US format or CTD ▪ No fees ▪ Required to register applicable trials in www.clinicaltrials.gov  ▪ CTA written approval required ▪ Approval timeframe varies ▪ Annual safety report only required Clinical Trials ▪ Format CTD paper or Application EU electronic ▪ National CTA fees may apply ▪ Competent Authorities will register clinical trial in EudraCT database  ▪ Form FDA 1572 is required to be signed by the PI, if study is conducted in US and submitted to IND ▪ Form FDA 3674 certification that all requirements of section 402(j) Conduct of of PHS Act are met Clinical Trials US ▪ Protocol amendments maybe implemented once received by FDA, with exceptions (e.g. safety issues or protocol study design issues) ▪ Protocol Waivers are acceptable under certain circumstances  Statement of Investigator not required by member states Conduct of Clinical Trials EU Protocol Amendment implementation varies upon classification (e.g., substantial vs. non- substantial) Protocol Waivers are considered a breach of GCP Investigational Product Requirements ▪ Label must be in English, except for Puerto Rico US ▪ The following statement is required: “Caution: New Drug Limited by Federal (or United States) law to investigational use” Investigational Product Requirements EU ▪ Label must comply with Annex 13 of EU Directive 2001/83/EC ▪ Language requirements varies between member states ▪ Sponsor is responsible for destruction of unused and/or returned IMP ▪ IMP batch records retention is ≥ 5 years after completion of CT or formal discontinuation of the last study in which the batch was used ▪ Retain sufficient samples of IMP and key packaging components used for each IMP finished product for ≥ 2 years after completion of CT or formal discontinuation of the last study in which the batch was used Adverse Event Reporting U.S. (1) ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ Adverse Event Reporting U.S. (2) ▪ ▪ ▪ ▪ ▪ ▪ Adverse Event Reporting EU (1) ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ Adverse Event Reporting EU (2) ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ KYMRIAH (tisagenlecleucel) FDA https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah- tisagenlecleucel EMA https://www.ema.europa.eu/en/medicines/human/EPAR/kymriah EMA Information / An overview of Kymriah and why it is authorized in the EU https://www.ema.europa.eu/en/documents/overview/kymriah-epar-medicine-overview_en.pdf / Summary product information https://www.ema.europa.eu/en/documents/product-information/kymriah-epar-product- information_en.pdf FDA Information / Product information https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah- tisagenlecleucel / Approval History, Letters, Reviews and Related Documents – KYMRIAH https://www.fda.gov/media/107978/download Globalization Annually and Globally >30, 000 trials > 66,000 Recruiting Studies > 50,000 participants (pivotal trials) > 200 countries No Time-out >10 trials/day > 15 sites/hour > 3 subjects/ minute ~90 subjects enrolled from the beginning of the presentation  CTA = Clinical Trial Application CTD = Common Technical Document Definitions IMPD = Investigational Medicinal Product Dossier IND = Investigational New Drug  Thank you Chaya Mazouz [email protected]