The process of new drug development involves a tremendous amount of non-clinical and clinical research, requiring collaboration among multiple stakeholders, such as researchers, clinicians, and Sponsors. However, before a new drug comes to market, it must undergo a rigorous approval process that evaluates its safety, efficacy, and quality. Additionally, it must meet all applicable legal and regulatory requirements. This process is performed by a pharmaceutical regulatory agency, which serves as an independent reviewer and approver of the applications submitted by Sponsors to conduct clinical trials for the development of a new drug. Each country has a drug regulatory agency, which issues guidelines and regulates various pharmaceutical products’ licensing, registration, manufacturing, and marketing.
This article summarizes the regulatory processes for new drug development performed by the FDA in the United States and several other major non-US pharmaceutical regulatory agencies. Additionally, we’ll outline the similarities and differences between foreign agencies as compared to the US FDA.
United States Food and Drug Administration (US FDA)
The US FDA regulates the approval of new pharmaceutical products in the United States. A Sponsor presents the results from a novel drug’s Chemistry, Manufacturing, and Controls (CMC) and non-clinical development program to the FDA in the form of an investigational new drug application (IND). The purpose of an IND is to provide detailed information to the FDA regarding drug manufacturing, animal pharmacology and toxicology studies, clinical study protocols, and investigator information. The FDA reviewers have 30 days to review the IND to determine if the clinical trials may be allowed to start. If the FDA does not object to the IND within this timeframe, clinical trials can begin. The drug progresses through sequential studies, i.e., phase 0 to phase III trials. Sponsors are allowed to conduct multiple studies under the same IND. Following the successful completion of these trials, a new drug application (NDA) is filed. The FDA reviews the application to determine if there is adequate evidence concerning the safety and efficacy of the drug and if it can be approved for marketing. Furthermore, the FDA reviews Post-marketing surveillance data following drug approval.
Drug approval times in the US: According to a recent report from the Centre for Innovation in Regulatory Science (CIRS), in the year 2020, FDA approved the highest number (50) of new active substances (NASs) among six major regulatory agencies of the world. The report also highlighted that the FDA had the shortest median drug approval time of 244 days.
European Medicines Agency (EMA)
Many of the processes performed to approve drugs in the European Union (EU) are identical to those in the United States. For instance, like the US FDA, the European Medicines Agency (EMA) requires a new drug to go through two significant regulatory steps before approval. These two steps include submitting and approving a clinical trial application (CTA) and a marketing authorization application (MAA).
However, a few dissimilarities exist in the drug approval process of these two regulatory authorities, which are discussed below:
Multiple member states: Unlike the US FDA, the EMA brings together the scientific resources of multiple member states of the European Union (EU). Member States approve CTAs, while MAAs are approved at both the member state and centralized levels.
Protocol-specific CTA: In contrast to an IND, a CTA is protocol-specific, and one CTA must be filed for each clinical study performed by a sponsor. An investigational medicinal product dossier (IMPD) is a separate document containing summaries of the drug’s CMC, non-clinical data, and an overall assessment of risks and benefits. Sponsors must submit the IMPD alongside the CTA.
Multiple registration processes: The new drug undergoes clinical trials analogous to those in the United States, following which a marketing authorization application (MAA) is submitted to the EMA for review. However, unlike FDA that follows a centralized path, MAA approval by EMA can occur through four different routes:
- Centralized process: The EMA issues a single license valid in all EU member states.
- Decentralized authorization procedure: Simultaneous approval of previously unapproved drugs in more than 1 EU state.
- National process: Approval of a drug based on the individual procedures of one EU member state only.
- Mutual recognition procedure: Expansion of approval of a drug already approved in a single EU state to other EU countries.
More time required for drug approvals: EMA drug review times are significantly longer than the US FDA. According to one study, for similar drugs, the median time for initial review was 303 days at the FDA and 366 days at the EMA. Similarly, the median times for full reviews were 322 days and 366 days for the FDA and the EMA, respectively. The study also showed that 63.7% of the drugs were brought to the market first in the US and were available a median of 90 days sooner to the US patients
Canada’s Therapeutic Products Directorate (TPD)
The drug regulation process in Canada is quite similar to that in the United States. The Therapeutic Products Directorate (TPD), an agency of Health Canada, is Canada’s counterpart to the US FDA and regulates all prescription and non-prescription drugs and medical devices for human use.
The process of drug approval begins by submitting a Clinical Trial Application (CTA) to the TPD. The application typically comprises the administrative form, clinical trial protocol, informed consent form, investigator’s brochure, and quality dossier summary. TPD notifies the Sponsor of the approval of the CTA within 30 days of submission. The different phases of clinical trials follow the approval. If the clinical trials generate sufficient evidence for the safety and efficacy of the new drug, the Sponsor may then decide to file a new drug submission (NDS). The NDS, analogous to an NDA, contains clinical trial information and details regarding the novel drug’s manufacturing, packaging, labelling, and adverse effects. The NDS initially undergoes an administrative screening procedure to determine if it contains all necessary information. This screening procedure is to be completed within 45 days of submission. Following the initial screening, the appropriate bureau in the TPD performs a thorough review of the data. It has 300 days to complete a standard NDS review and 180 days for a priority NDS review.
Regulatory review times compared to the US: Studies have shown that the regulatory review times for the applications for novel therapeutic agents are longer in Canada than in the United States. In a study comparing the regulatory review times between Health Canada and the FDA, the median time for the first review was 49 days longer, and the total review time was 71 days longer for Health Canada. In addition, first-to-market times are longer in Canada, with 85.7% of the drugs getting approved first in the US and becoming available in the US markets a median of 355 days sooner than in Canada.
Japan’s Pharmaceuticals and Medical Devices Agency (PMDA)
The new drug approval process in Japan is similar to that in the US, with the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), a part of the Ministry of Health, Labour, and Welfare (MHLW) being responsible for ensuring the safety, efficacy, and quality of drugs and medical devices in the country. Like the FDA and EMA, the PMDA follows the Common Technical Document (CTD) drug application format, which the Sponsor must follow to prepare and submit an investigational new drug (IND) application. The initial IND consultations may take around 30 days, during which the PMDA evaluates the preclinical data, clinical trial protocols, and other essential documents. Upon completing the review, the Sponsor seeks approval from the Institutional Review Board (IRB), which can take about 1-4 weeks. After receiving IRB approval, the Sponsor may commence human clinical trials.
Upon completing a clinical trial, the applicant submits a new drug application (NDA) to the PMDA for review. The results of the review are sent to the MHLW, which may then approve the NDA.
Safety triangle: PMDA focuses on comprehensive risk management through three essential functions: product reviews, post-marketing safety measures, and relief services for health damage caused by adverse drug reactions. Providing relief compensation for individuals who suffer from adverse health effects resulting from a pharmaceutical product makes this “safety triangle” unique to Japan.
Drug approval times compared to the FDA: According to the CIRS, PMDA approved 31 new active substances (NAS) in the year 2020, with a median approval time of 313 days, which is 69 days longer compared to that of the FDA.
China’s National Medical Products Administration (NMPA)
The National Medical Products Administration (NMPA), formerly the China Food and Drug Administration (CFDA), is directly under the State Council of the People’s Republic of China and regulates drugs and medical devices. The drug approval process involves submitting a clinical trial application (CTA) by the Sponsor to the NMPA. Clinical trials may be started following CFDA’s approval. After completing the trials, the applicant can submit the drug marketing authorization application. This application must be approved by NMPA’s Center for Drug Evaluation (CDE) if all the requirements are met.
In recent years, the Chinese government made revolutionary changes in drug research and development and has attempted to reshape its clinical trial approval system to become similar to that of the US. The two most impactful initiatives are:
- Quicker approval times for CTAs: In the past, it took around 2-3 years to approve a clinical trial application (CTA). However, now, a 60-working day period applies to all CTA approvals. If the Sponsor does not receive a response from the NMPA in 60 days, the application is automatically approved.
- Accelerated drug approval pathways: Like the FDA, China’s NMPA has established multiple fast tracks to facilitate expedited drug approval, particularly for drugs with significant therapeutic value. These pathways include breakthrough therapy designation, conditional approval, special approval, and priority review.
Reduction in the drug lag: China’s significant regulatory reforms resulted in faster drug approval times and led to an increased number of drug approvals in recent years. For instance, in the year 2016, only five drugs were approved in China. In 2017, this number rose to 40, while in 2018, 52 new drugs were approved. While the drug lag remains, it is significantly reduced, with some drugs now being approved within a year of receiving approval in the US and Europe.
Australia’s Therapeutic Goods Administration (TGA)
The Therapeutic Goods Administration (TGA) is the drug regulatory body in Australia, and it is a part of the Department of Health. The TGA approves prescription and non-prescription drugs that meet Australian quality, safety, and efficacy standards. Following approval by the TGA, the drugs are included in the Australian Register of Therapeutic Goods (ARTG).
Sponsors seeking approval of a new drug in Australia must submit a clinical trial application for conducting human trials. Furthermore, a clinical trial conducted in Australia must have an Australian sponsor. There are two major pathways for the submission of clinical trial proposals:
- Clinical trial notification (CTN): Under this scheme, the application is submitted to the Human Research Ethics Committee (HREC), which provides approval after a scientific and ethical review. The clinical trials can commence after due notification to the TGA.
- Clinical trial approval (CTA): In the CTA scheme, formerly known as the clinical trial exemption (CTX), a Sponsor will submit an application directly to the TGA, which must review the data and provide approval to conduct the proposed clinical trial.
Following the completion of clinical trials, an application is submitted to TGA to register the new drug in the ARTG. The application comprises data supporting the safety, efficacy, and quality of the novel drug. The application is thoroughly reviewed, and a delegate within the TGA, after due advice from the Australian Drug Evaluation Committee (ADEC), decides to approve or reject the drug.
Median drug approval time as compared to the FDA: According to the latest CIRS report, TGA approved 27 new active substances (NASs) in 2020. The median approval time was 315 days, which is 71 days longer than the median approval time of the US FDA.
In conclusion, while the primary approach for approving a new drug is comparable throughout the world, the exact regulatory process varies from one country to another. Also, a significant amount of variation in the drug approval times is observed. However, it is essential to understand that the primary purpose of the drug regulatory processes is to safeguard public health. By ensuring strict compliance with the applicable regulations and guidelines, every pharmaceutical regulatory agency ensures the delivery of safe, efficacious, and high-quality drugs to the public.
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