Emergency use authorization of medicines: History and ethical dilemma

Abstract

The regulatory approval process of the United States Food and Drug Administration and European Union is the most demanding and challenging worldwide. They have the provision of the expedited approval pathways, i.e., “Emergency use authorizations” and “Conditional marketing authorizations,” respectively, to give approval to novel therapeutics agents during emergency situations. India, firstly formalized the accelerated pathway named “Accelerated Approval Process” as per the New Drugs and Clinical Trials rule 2019 to address unmet medical needs that was implemented by the Central Drug Standard Control Organization to approve the novel therapeutics agents during COVID-19. Hence, our aim is to understand and compare the different emergency approval processes in the world, their underlined claims and conditions with the list of approved products under this concept. All the information collected and analyzed from different official websites of regulatory bodies. In this review, we have enlightened on all these processes with their few approved products.

INTRODUCTION

To strengthen the nation’s public health, different regulatory authorities are working that not only provide guidelines for drug marketing but also enforce the rule and regulations. The drug approval process is a protracted and tedious process requiring much data, but the scenario changes during a pandemic, or epidemic when any type of nuclear, radiological, biological, or chemical, an emergency occurs. During such situations regulatory bodies authorizes unapproved drugs based on certain parameters in the context of public health. To counteract these situations regulatory authorities worldwide expedited the approval process and set up the guidelines or pathways for unapproved drugs, which can be a game changer in life-threatening or serious conditions.

CORONAVIRUS (COVID-19) PANDEMIC

In late December 2019, the first case of the virus was found in Wuhan, Hubei Province, China, and spread fast worldwide in a short period. The culprit behind this COVID-19 is a highly contagious disease caused by severe acute respiratory syndrome coronavirus-2. During the corona pandemic, the complete and partial lockdown was imposed worldwide that adversely affected not only the health-related quality of life, socioeconomic status, education, farming, and industry but also the country’s economy as manufacturing, supply chain, transportation, and distribution of products and services was hampered. This virus had a disastrous effect on the world’s sociodemographics that lead to more than 3.5 million deaths worldwide. Hence, on March 11, 2020, the World Health Organization (WHO) declare it a global pandemic, according to the report of a worldometer worldwide.[1]

Hence, here we will not only compare the emergency use authorization (EUA) procedure among the United States Food and Drug Administration (USFDA), European Union (EU), and India but we will also look into the history of such category drugs with their pro and cones.

EMERGENCY USE AUTHORIZATION – UNITED STATES FOOD AND DRUG ADMINISTRATION

The USFDA commissioner has sovereignty over for the issuance of the EUA, but after considering and consulting the prevalent conditions and indications with the secretaries of different departments as the case may be. The emergency may be categorized as military, domestic, public health, or related to a material threat. Depending on the area or sector concerned, the respective secretary is approached and a decision over EUA is taken while considering the Federal Food, Drug, and Cosmetic Act, section 564 as shown in Figure 1. Different departments and secretaries under USFDA are:

Figure 1.

Flow chart for issuance EUA under USFDA

1. The Department of Defence (DoD): At the time of a military emergency or striking risk the military DoD secretary issues a declaration of EUA

2. The Department of Homeland Security (DHS): Whenever there is an internal emergency or exceptional risk of a domestic emergency, the DHS secretary will issue a declaration like a material threat declaration

3. The Department of Health and Human Services (HHS): At the time of any potential risk or public health emergency (PHE) the secretary of HHS will issue a declaration

4. The DHS secretary releases a material threat determination.[2]

The Food and Drug Administration (FDA) commissioner consult with the HHS, the Center for Disease Control and Prevention, the Assistant Secretary for Preparedness and Response, and the National Institutes of Health, before providing the EUA, if the criteria are met. The FDA publishes all information about EUA for public awareness in the federal register.[3,4] To avoid and overcome such emergency situations, when no suitable, approved alternatives are available, the use of either unapproved medical products or approved medical product’s unapproved uses also known as drug repurposing are allowed to use in serious or life-threatening diseases or conditions.

Criteria and conditions for emergency use authorization

The process of EUA is expedited based on different evidence of preclinical, clinical studies, and trials while considering its efficiency, efficacy, intended use, and benefit-risk outweigh ratio. The normal marketing approval process is comparatively long.

1. EUA strictly required physicians and hospitals to keep records of the allocation and dispensing of such drugs specifying each and every piece of information, like how to use the product, whom will be administered and through which route, and in what amount with the frequency of dosing

2. EUA follows the firm labeling restrictions that not allowed to mention or suggest that the drug is effective and safe for the current emergency as lacking thorough study in highly complex conditions, comorbidities, and pregnant women, so used only under the terms of the EUA-FDA

3. The informed consent form is an important part of the EUA as it is considered a fact sheets of the product, shared with patients by the health-care professionals

4. MedWatch reporting system of the FDA allows clinicians to report any medication error and serious adverse events associated with the said drug immediately.

Such type of EUA is valid on the basis of certain statutory criteria, up to the circumstances that justify it or when the US government declares so. The EUA authority of the USFDA allows for facilitating the availability of medicinal product and medical countermeasures during any pandemic or PHE, few examples are shown in Table 1.

Table 1.

The list of emergency approved products during COVID-19

Product name	Developer	Approval date
USFDA - Emergency use authorized approved products
Molnupiravir	Merck and Ridgeback’s	December 23, 2021
Paxlovid	Pfizer’s	December 22, 2021
Evusheld	AstraZeneca’s	December 8, 2021
Propofol-Lipuro 1%	Fresenius Kabi	March 12, 2021
Bamlanivimab and etesevimab	Eli Lilly	February 9, 2021
REGEN-COV	Regeneron Pharmaceuticals	November 21, 2020
Baricitinib	Eli Lilly and Comp.	November 19, 2020
COVID-19 convalescent plasma	By HHS, U.S.	August 23, 2020
Remdesivir	Gilead sciences	May 1, 2020
EMA - Conditional marketing authorized products
Comirnaty	BioNTech and Pfizer	December 21, 2020
Janssen’s COVID-19 vaccine	Janssen-Cilag International NV	March 11, 2021
Nuvaxovid	Novavax CZ, a.s.	December 20, 2021
Spikevax	Moderna Biotech Spain S.L.	January 6, 2021
Vaxzevria	AstraZeneca AB	January 29, 2021
Paxlovid	Pfizer	January 28, 2022
Kineret (anakinra)	Biovitrum	December 17, 2021
Evusheld	AstraZeneca	March 25, 2022
Regkirona (regdanvimab)	Celltrion Healthcare	November 12, 2021
RiActemra (tocilizumab)	Hoffmann-La Roche and Chugai	December 7, 2021
Ronapreve	Roche Registration GmbH	November 12, 2021
Veklury (remdesivir)	Gilead Sciences	July 3, 2021
Xevudy (sotrovimab)	GlaxoSmithKline Trading Services Limited	December 17, 2021
CDSCO - India restricted emergency use authorized products
ZyCoV-D (rDNA vaccine)	Cadila Healthcare Ltd.	April 26, 2022
SPUTNIK light (recombinant vaccine)	Heteros Biopharma Ltd.	March 16, 2022
SPUTNIK light	Dr. Reddy’s Lab. Ltd. (Importer)	February 5, 2022
CORBEVAX*	M/s Biological E Limited	December 28, 2021
COVOVAX	SII	December 28, 2021
Molnupiravir (antiviral drug)	Aurobindo Pharma Limited	December 28, 2021
Covaxin	M/s Bharat Biotech	December 24, 2021
SPUTNIK-V (gam COVID vaccine)	M/s Hetero Biopharma Ltd	October 7, 2021
ZyCoV-D (recombinant DNA)	Cadila Healthcare Limited	August 20, 2021
Janssen vaccine	Biological E Limited	August 18, 2021
Janssen vaccine	M/s Johnson and Johnson Pvt. Ltd. (Importer)	August 7, 2021
SPUTNIK-V	M/s Panacea Biotec Ltd	July 2, 2021
Moderna vaccine mRNA vaccine	M/s Cipla Ltd. (Importer)	September 29, 2021
SPUTNIK-V (recombinant vaccine)	M/s Dr. Reddy’s Lab. Ltd. (Importer)	April 12, 2021
Covaxine	M/s Bharat Biotech	January 3, 2021
Covishield	M/s Serum Institute of India Pvt. Ltd. and AstraZeneca	January 3, 2021

*Corbevax is a made-in-India vaccine research and developed by biological E Hyderabad-based company and it is the cheapest vaccine available in the market for now for one dose (From: https://cdsco.gov.in/opencms/opencms/en/Notifications/Public-Notices/). HHS=Health and human services, SII=Serum institute of India, USFDA=United States Food And Drug Administration, EMA=European medicines agency

The public health services act, section 319 covers the law for PHE. During COVID-19, the HHS secretary declared the emergency on February 4, 2020, by observing the significant potential risk of PHE that not only affect national security but also the health and security of the US people living in other countries.[5] If appropriate and needed, the FDA can terminate the declaration and EUA. In such postemergency situations, drugs and biologics approved by the emergency pathway cannot be used[6] and the applicant needs to follow the standard drug approval pathway of the USFDA which is like filling of Investigational New Drug Application (IND) and New Drug Applications (NDA).

CONDITIONAL MARKETING AUTHORIZATION – EUROPEAN UNION

In EU, there are 27 countries but for the approval of medicinal product their regulatory authority European Medicines Agency (EMA) works with scientific committees such as Committee for Medicinal Product for Human Use (CHMP) and Pharmacovigilance Risk Assessment Committee. They together work for the approval of medicinal products with special emphasis on safety and risk minimization, and accelerated procedures of marketing authorization known as conditional marketing authorization. Such procedure support research and development by evaluating medicines, biologics (vaccines), and treatments not only for COVID-19 but for other emergencies also. The rapid approval process of EU has four steps,[7] as shown in Figure 2:

Figure 2.

Expediated approval pathway EMA

1. The rolling reviews

2. Application submitted for conditional marketing authorization (CMA)

3. Procedure review by EMA’s scientific committee

4. Approval discussion by EMA on whether to grant CMA or not.

Whenever there is any PHE, EMA starts evaluating clinical data as soon as possible for the promising medicine as the clinical data continue to emerge EMA needs to conduct several rolling review cycles. Once the entire clinical data are available and are verified and reviewed for the quality, safety, and efficacy of the drug after then the company/sponsor can formally apply for marketing authorization application (MAA) to the EMA. CMA plays an important role during public health emergencies to save lives as it speedily approves the medicine/biologic so known as fast-track authorization. PHE or pandemic may emerge due to severely contagious or life-endangered diseases. CMA is accepted when the available data of the treatment shows benefits outweigh its risks, in such conditions with less comprehensive data (pharmaceutical and nonclinical data) market authorization is approved to address the unmet medical needs of patients. In such conditions, the applicant will provide the all required comprehensive clinical data as per the general approval process in the future.

Criteria and Conditions for conditional marketing authorization

If medicine fulfilled all of the following criteria then CMA is granted to the sponsor:

• The benefit-to-risk ratio, of medicine must be positive

• In the future postauthorization, whether the applicant would be in a position to provide comprehensive clinical data or not

• Unmet the medical need of the patients must be fulfilled by the medicine

• If the medicine’s immediate availability to patients is more beneficial than the risk of not providing additional data.[8]

Such medicine/biologics approved under CMA, initially remain valid for only 1 year and can be renewed annually. Once the CMA is granted, to convert it into standard centralized MAAs, the marketing authorization holder, must fulfill the obligation imposed by the EMA within the defined timeline. These obligations are required to prove that the benefit–risk ratio of the medicine/biologics still remains positive after analyzing the additional compiled data of all pending trials and research. EMA timely publishes the list of medicine/biologics in the European public assessment report, to which the CMA is granted. In an emergency situation, when CMA is provided to the sponsor without any specific obligations for 5 years, it can be reviewed against a standard marketing authorization and renewed for unlimited validity. EMA can take regulatory action either by suspending or revoking the marketing authorization if the new data of any medicine/biologic’s benefits no longer outweigh its risks or if the company or sponsor does not comply with the obligation imposed by the regulatory authority.[9] During the COVID-19 pandemic, this fast track authorization pathway or CMA was widely used to grant access to safe and effective COVID-19 vaccines to all EU citizens simultaneously and to support mass vaccination campaigns as shown in Table 1.

Guidance for applicants for conditional marketing authorization

For speedy submission, and to figure out necessary steps and documents EMA advises applicants to arrange a presubmission meetings with scientific advice or protocol assistance to discuss their development plans. It helps them to understand the development of medicine/biologics, and whether CMA will be granted to them or not. The applicant must indicate in their notification as well as the request of CMA, about the submission of MAA. Applicant can submit their request 6 to 7 months before submitting the application. Under exceptional circumstances of authorization, unlike CMA the applicant need not to provide the comprehensive data postauthorization.[10]

INDIA: RESTRICTED USE IN EMERGENCY

Central Drug Standard Control Organization (CDSCO), the regulatory authority in India takes care of all the approval processes. To address novel pandemics or public health emergencies were taken care of by the Ministry of Home Affairs through the National Disaster Management Act of 2005 and the Ministry of Health and Family Welfare through the Epidemic Diseases Act of 1897[11] like USFDA regulation. We initially does not have expedited pathway to respond to PHE, India’s first time formalized accelerated approval pathway came into effect in the form of New Drugs and Clinical Trials (NDCT) rules 2019, under the Drugs and Cosmetic Act 1940 and Rules 1945 by CDSCO.[12,13]

In view of the COVID-19 surge in India, by keeping the suspension rules 81 and 83 of the NDCT act 2015 Rules, 2019 regulator allowed “Accelerated Approval Process” permission for a few drugs and also issue a formal notification for the manufacture of novel vaccines. In the same context, on April 11, 2021, the National Expert Group on vaccination for COVID-19 decided that the if foreign produced vaccine for COVID-19 was already approved by USFDA, EMA, United Kingdom’s Medical and Healthcare Products Regulatory Agency (UKMHRA), Pharmaceuticals and Medical Devices Agency (PMDA) in Japan for restricted use, and any drug that is WHO listed for emergency use, then Drug Controller General of India (DCGI) will issue permission for the same as shown in Table 1.

Condition supporting restricted emergency use

1. All the vaccine which gets authorized shall follow the guidelines mentioned under COVID-19 vaccination programs

2. The first 100 recipients vaccine shall be assessed for 7 days to evaluate their safety before they launch the vaccination program

3. The applicant shall initiate a clinical trial within 30 days of such approval.[14]

Procedures for approval of COVID-19 vaccine under restricted emergency use

1. Submission of application: Application shall be made as per the Drug and Cosmetics Act 1940 by the foreign manufacturer through its Indian subservient or authorized agent in India

2. The application can be submitted via “SUGAM” portal online along with stipulate fees and common technical document (CTD).

3. Applicants can also submit registration certificate application and import license application along with the Restricted emergency use (REU) application as shown in Figure 4.[2]

4. Processing of application: CDSCO will evaluate such application at the highest priority through the accelerated review process if required will guide on such matters for the regulatory pathway, and DCGI will consider the application and made a decision whether to grant REU or not within three working days from the REU application submission date[15]

5. CDSCO after REU application approval, evaluate the registration certificate and import license applications submitted by the applicant and make the decision within three working days after the approval of the vaccine

6. Once the import license is granted, according to the CDSCO, the current protocol before using vaccine as per the vaccination program applicant needs to get every imported batch of vaccine must be tested at Central Drug Laboratory, Kasauli

7. The safety data submitted by the applicant will be reviewed by CDSCO and once found satisfactory, will authorize the applicant to use the vaccine under the COVID-19 vaccination program as shown in Figure 3.[16,17]

Figure 4.

REU authorization procedure steps

Figure 3.

Flow chart showing standard and expediated approval pathway EMA

The concluding comparison of all three processes, namely, USFDA, EMA, and CDSCO’s with their applicable criteria and conditions with their limitations or end of these temporary measures are discussed in tabular form as follows in Table 2.[18,19]

Table 2.

Comparison of schemes among the United States Food And Drug Administration, European Medicines Agency and Central Drug Standard Control Organization

Criteria	EUA (USFDA)	European Union conditional marketing authorization	Accelerated approval process (India)
Objective	Nation’s public health protection by promoting availability of medical counter measures against radiological, biological, nuclear, and chemical threats	To addresses unmet medical needs immediate availability of the medicinal products on the market outweighs the risk of having less comprehensive data available	To addresses unmet medical needs deliberated for the treatment of a serious or life-threatening condition or disease of special pertinence to the country
Legal basis	Federal food, drug and cosmetic act section 564 (the act) (21 U.S.C. 360bbb-3)	Com Reg (EC) No 507/2006	New drugs and clinical trial act 2015 rules 2019 under Drug and Cosmetic act 1940
Requirements	HHS secretary declares the public health emergency that give justification for the emergency use of medical counter measures (e.g., vaccine, antidote, drugs, or diagnostic)	Positive benefit-risk balance of the product with the comprehensive data of the product unsatisfied medical need must be fulfilled; public health benefit of the medicinal product; instant availability on the market outweighs the risk	Appeared emergency, unsatisfied medical need, beneficial to patients, availability of the drug and with a remarkable efficacy, as per the NEGVAC recommendations: already having emergency approval for restricted use by USFDA, EMA, UK MHRA, PMDA Japan or listed in WHO’s emergency use
Approved alternatives	No approved alternative	Unmet medical needs	No approved alternative
Duration	No specific duration limit	Valid for 1 year renewable	Valid for 1 year/renewable
Patient consent required	Not required	Not required	Not required
Pharmacovigilance measures	Either a company or a patient directly reports the ADR to FDA through MedWatch	Registered medical practitioner and general safety reporting. Postapproval efficacy and/or safety studies may be included in specific obligation imposed by authority	Case should be investigated by the district health authorities (DIO) with the support of the National AEFI committee members PIE within 6-12 months following the introduction of the new vaccine
Product distribution	Depending upon the pandemic status, US government distributes the medicinal product	Possible restriction of prescriptions; distribution controlled by MAH	Depending upon the pandemic status on the state and need in regions
End of temporary measures	EUA is no longer needed either when the approval status of the product change or on the recommendation of the secretary that the EUA no longer exist	Yearly review; depend upon new data modified or withdrawn may occur; conversion into normal marketing authorization upon fulfilling the obligation imposed by the regulatory authority	After reviewing the result of the bridging clinical trial, the DCGI found satisfactory result may granted restricted use in an emergency situation

FDA=Food and drug administration, USFDA=United States FDA, HHS=Health and human services, ADR=Adverse drug reaction, EUA=Emergency use authorization, MAH=Marketing authorization holder, NEGVAC=National Expert Group On Vaccination For COVID-19, EMA=European medicines agency, MHRA=Medicines and healthcare products regulatory agency, PMDA=Pharmaceuticals and medical devices agency, WHO=World health organization, DIO=District immunization officer, AEFI=Adverse event following immunization, PIE=Postintroduction evaluation, DCGI=Drug controller General of India

CONCLUSION

During the “PHE” COVID-19, precaution and administration of vaccine significantly reduced the number of COVID-19 patients worldwide. Despite the fact of the immediate requirement of the vaccine to control the crisis, we cannot forget that the vaccine must be safe and effective for human use. The WHO along with the regulatory authority has taken several step to ensure the availability of medicine/biologics worldwide. Regulatory authorities adopted “Emergency use authorization pathways” to approve medicinal products/biologics on the basis of outweigh benefit–risk ratio after ensuring their proper safety and quality in different clinical trials. Despite all these expedited processes, we consider it an ethical dilemma for regulatory agencies to compromise with the actual approval process to deal with unmet medical needs in which they are not 100% sure about product safety, efficacy, and quality. Product approved by these pathways with the objective to ultimately reduce the approval time during PHE-like COVID-19 and under other certain conditions.

In the Indian context, there is a need for not only well-drafted, transparent, authentic decision-making procedures based on the prevalent conditions, but also bolstered research of academicians, legitimization of the company’s claim on its drug product, helped health-care professional to access evidence pertaining to their medical practice.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.