The differences in regulatory requirements across regulatory authorities is an impediment to speedy drug development. To address this concern, the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) have undertaken several steps to seek convergence on the regulatory requirements to minimize the impact on drug development programs.
While it would be ideal to have completely harmonized requirements across all regulatory authorities, it is important to recognize that this is probably not a realistic expectation, considering the different regulatory and legal frameworks under which
the agencies operate.
This chapter takes a look at the various submission types and data requirements during clinical investigation and marketing approval stages, pointing out the similarities and differences between the various marketing regions of the world.
Drug Application Types in the US
Two important submission types for new drug development in the US are the investigational new drug application (IND) and the New Drug Application (NDA). While clinical investigations of a new molecule must be conducted under an investigational new
drug (IND) Application to assess its safety and efficacy, the marketing approval is obtained through an NDA submission process.
Investigational New Drug Application
Submitting an IND to the FDA is a key milestone in developing a new drug for the US market. Before any clinical trials can start, Form FDA-1571 must be completed and submitted to the FDA.1 Indeed, US Federal law requires that a drug be the subject of an approved marketing application such as an IND before it is transported or distributed across state lines. Thus, filing an IND application enables a sponsor to ship an experimental drug between the states, which is important when conducting multi-center studies.
According to the FDA, the primary objectives of the IND review process are, “in all phases of the investigation, to assure the safety and rights of subjects, and, in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to
permit an evaluation of the drug’s effectiveness and safety”.1
Investigational New Drug Application
Submitting an IND to the FDA is a key milestone in developing a new drug for the US market. Before any clinical trials can start, Form FDA-1571 must be completed and submitted to the FDA.1 Indeed, US Federal law requires that a drug be the subject of an approved marketing application such as an IND before it is transported or distributed across state lines.Thus, filing an IND application enables a sponsor to ship an experimental drug between the states, which is important when conducting multi-center studies.
According to the FDA, the primary objectives of the IND review process are, “in all phases of the investigation, to assure the safety and rights of subjects, and, in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety”.
Types and categories of IND
The FDA recognizes three types of INDs – Investigator INDs, Emergency Use INDs, and Treatment INDs – and two categories of INDs – Commercial INDs and Research INDs.2
Looking first at the different types, an Investigator IND is one that is submitted by a physician or group of physicians who are looking to study the effects of a drug, approved or unapproved, in a specific patient population or for a new indication.2
An Emergency Use IND may be granted when there is not enough time for the usual IND submission process. This may be where there is an urgent need that is in the public health interest or a patient needs to be treated urgently as there are no other options.2 A recent example of an Emergency Use IND being granted is the authorization for vaccines to prevent COVID-19 in line with stipulations set out in 21 CFR Section 312.1,3
Finally, the purpose of a Treatment IND is to make an unapproved drug available for the treatment of serious or immediately life-threatening condition. This type of IND is submitted before an NDA or biologic license application (BLA).2
As for the different categories, Commercial INDs are those which are submitted by companies to gain permission to market a new medication whereas researchers submit Research INDs.2
Content and submission
The content and submission of the IND follows the common technical structure (CTD) developed by the International Council for Harmonisation on Technical Requirements for Pharmaceuticals for Human Use ICH.
Details that must be included in an IND application are:1
•Information on the investigational drug’s pharmacology and toxicology, based on nonclinical testing (see Chapter 6). This includes information on its mechanism of action and likely efficacy in specific indications;
•The manufacturer and manufacturing process, including such details as the drug’s composition and stability, and the manufacturing controls to be used;
•Clinical protocols to be used: a first-in-human protocol is commonly a single ascending dose design;
•Investigator information, including names and qualifications of the professionals (generally physicians) who will supervise the administration of the investigational drug;
•Investigator’s Brochure, giving information on the investigational drug so that a clinical trial can be conducted safely.
Beginning clinical trials
Before any clinical trials can begin, the sponsor must wait 30 calendar days after the IND has been submitted.2 This allows the FDA time to review the application and evaluate whether there is enough data to permit the investigational drug’s safe administration to humans. It also enables the FDA to gauge whether trial
subjects’ rights are guaranteed to be protected.
INDs are not approved; instead, they become effective 30 days after they are received by the FDA. That is unless the FDA finds any reason to place the proposed trial on full or partial clinical hold.5 When an application is put on hold, it means that there are significant safety concerns regarding the use of the investigational.5 A complete clinical hold is when all clinical work requested under the IND is delayed or suspended, whereas a partial clinical hold is when only part of the clinical work is delayed or suspended. A hold may also mean that the investigational drug should not be given to study subjects, or that no new participants can be recruited if the study is on-going.5 The sponsor should provide a ‘complete response’ to the issue(s) raised by the FDA in writing.5 The FDA will then review sponsor’s response and determine whether the issues raised have been adequately addressed to enable the IND application to be re-opened.5 If the response is considered adequate, the sponsor can then conduct human clinical trials based on the protocol detailed within the IND.1,5
Amendments and reports
When a drug is undergoing development, the IND needs to be updated regularly.6 Annual reports need to be submitted to the FDA and should serve as the focus for reporting the status of studies being conducted under the IND and inform the general investigational plan for the coming year. Subsequent amendments to the IND that contain new or revised protocols s
hould build logically on previous submissions and should be supported by additional information, including the results of animal toxicology studies or other human studies as appropriate.
New Drug Application
The NDA is the formal means by which drug sponsors request that the FDA approves a new pharmaceutical drug for sale and marketing in the US.7
An NDA must contain all information regarding an investigational drug, including nonclinical and clinical trial results and details of its manufacturing, so that the FDA can evaluate the drug’s safety, efficacy and quality as a pharmaceutical product.
Reports on all studies, data, and analysis must be included by the sponsor and the sponsor must provide details on:
•Proposed labeling
•Safety updates
•Drug misuse potential
•Patent information
•Any data from studies that may have been conducted outside of the US
•Institutional review board compliance information
•Directions for use
The NDA consists of a cover letter and a completed Form FDA-356h with other supportive documentations.7 21 CFR § 314.50 describes the content and format of an NDA; for a new chemical entity, this states that the NDA “generally contains an application form, an index, a summary, five or six technical sections, case report tabulations of patient data, case report forms, drug samples, and labelling”. The NDA should also include the data obtained during nonclinical and clinical trials that were included in the preceding IND. (See Table 15-1)
After it has been submitted, the sponsor can expect to wait up to 60 days for the FDA to perform its preliminary evaluation of the NDA and determine whether it is “sufficiently complete to permit a substantive examination”.8 If the FDA deems that the NDA is not sufficiently complete, the application will be rejected, with a ‘Refuse to File’ letter being sent to the sponsor.
This letter will specify which requirements of the NDA that the application did not meet. However, if the FDA issues a ‘Complete Response Letter’ this means that the NDA cannot be granted for substantive reasons.
If the application is accepted for filing, the FDA decides whether the NDA requires a standard or accelerated review. This decision will be communicated to the sponsor within 74 days and the review of application will be performed based on performance goal dates listed in the Prescription Drug User Fee Act (PDUFA) VII.9
Conducting Clinical Trials in the EU
The assessment of an investigational drug for the conduct of clinical trials and obtaining marketing authorization in the EU is carried out by EMA’s Committee for Medicinal Products for Human Use (CHMP). Sponsors need to adhere to legislation as set out in volume 10 of the EudraLex10 and submit a Clinical Trial Application (CTA). CTA submission in EU is equivalent to an IND submission in the US. The Investigational Medicinal Product
Dossier (IMPD) is one of the essential documents of a CTA.
EU legislation for Clinical Trials
