/>iThe Coronavirus (COVID-19) pandemic poses an acute health risk to the population. One key to successfully combating COVID-19 lies in clinical research. Currently, almost all major research-based pharmaceutical companies, many other pharmaceutical and biotech companies, and research institutions worldwide are engaged in a race to develop effective drugs and vaccines against COVID-19 in preclinical and clinical research. In the field of therapeutic drugs, hopes are pinned not only on the development of new drugs, but also on the repurposing of drugs developed for other infectious diseases that are currently undergoing clinical trials or are already approved. In the field of vaccines to be given to healthy people, the requirements for proof of safety and efficacy are particularly high, and there are strict limits to testing before approval. The development of effective vaccines and therapeutics is a race against time, even as the pandemic makes it considerably more difficult to conduct clinical trials.
Against this backdrop, US and EU regulators provide several options for action and procedural facilitations that aim to enable faster access to effective drugs and vaccines to combat the pandemic. This article gives a high-level overview of strategic tools available to research companies and institutions in both jurisdictions.
IN DEPTH
Regulatory Framework in the United States
In the United States, the US Food and Drug Administration (FDA) is the primary agency responsible for the oversight of drugs, biological products and vaccines. In general, developers of therapeutic products and vaccines must obtain approval from the FDA prior to investigating or marketing such products. The following overview focuses on pathways and initiatives that may facilitate or expedite access to, or the development of, COVID-19 therapeutics and vaccines in the United States.
Off-Label Use of an Approved Product
In general, once the FDA has approved a drug or biological product, healthcare providers may prescribe or approve the drug for an unapproved use (i.e., an off-label use). As a result, healthcare providers can typically decide whether to prescribe an existing approved drug “off-label” without FDA oversight, subject to the provider’s assessment of the potential benefits versus the risks for the patient, prevailing professional standards of practice and potential liability considerations.
Emergency Use Authorization
During a public health emergency, the FDA may use its Emergency Use Authorization (EUA) authority to permit the use of unapproved medical products, or the off-label use of approved medical products, to diagnose, treat or prevent serious or life-threatening diseases when certain criteria are met. These criteria include a requirement that no adequate, approved and available alternatives exist.
Before the FDA can issue an EUA for any specific product, the Secretary of Health and Human Services must make a declaration of emergency or threat justifying authorisation of emergency use. On 4 February 2020, the Secretary made this determination with respect to COVID-19. On the basis of this determination, the Secretary subsequently declared that circumstances exist justifying the emergency use of certain FDA-regulated therapeutic products, as well as certain medical devices (e.g., personal protective equipment, in vitro diagnostic tests and ventilators).
Investigational New Drug Applications
In general, a therapeutic or vaccine sponsor must obtain an approved investigational new drug application (IND) before beginning clinical (human) trials. However, therapeutic and vaccine developers should seriously consider asking the FDA for a pre-IND meeting (or pre-IND written feedback). Pre-IND interactions give product developers an opportunity to obtain regulatory feedback on proposed development plans. They may reduce time to market by identifying unnecessary studies and ensuring that studies are designed to provide useful information, and can gain the agency’s support for a particular development strategy.
FDA is expediting the provision of pre-IND feedback and the review of INDs for sponsors seeking to develop COVID-19 vaccines.
Expanded Access Program
Sometimes called “compassionate use”, the FDA’s expanded access program describes a group of programs intended to give patients with an immediately life-threatening or serious disease or condition access to an investigational therapeutic product outside the scope of a clinical trial when no comparable or satisfactory alternative therapeutic options are available. There are three types of expanded access programs under existing FDA regulations, depending on the size of the patient population for which expanded access is sought: expanded access for individual patients (including for emergency use), for intermediate-size patient groups, and for widespread treatment use through a treatment IND or treatment protocol.
For example, under the National Expanded Access Treatment Protocol, the FDA has authorised expanded access for use of COVID-19 convalescent plasma for patients with serious or immediately life-threatening COVID-19 who are not eligible to participate in randomised controlled trials.
Coronavirus Treatment Acceleration Program
One additional avenue for therapeutic product developers to consider is the FDA’s Coronavirus Treatment Acceleration Program (CTAP), which is a special emergency program intended to expedite the development and approval of possible therapies for COVID-19. Under this program, FDA will triage requests from developers and scientists who are developing or evaluating new drug and biological therapies, connect developers with appropriate FDA staff, and provide rapid interactive input on product development plans and/or study protocols. The CTAP is not available to vaccine developers, however. Vaccine developers are expected to go through the usual pre-IND/IND process before starting clinical trials.
Regulatory Framework in the European Union
In Europe, the authorities competent for the marketing authorisation of drugs and vaccines are the European Medicines Agency (EMA) at the EU level and the respective national drug authorities at the Member State level. Generally, pharmaceutical companies may obtain a marketing authorisation for their drugs either by way of a centralised procedure before EMA (aimed at obtaining an EU-wide marketing authorisation) or by way of national marketing authorisation proceedings. The following overview focuses on possible actions and procedural simplifications provided by EMA.
Off-Label Use
Several drugs that have not been approved for use—either at all or in the context of COVID-19—are being used to treat severely ill COVID-19 patients. For authorised drugs, use outside the approved indications (off-label use) is acceptable under certain conditions. EU-level law does not stipulate guidelines for off-label use, and regulations at the Member State level vary to some extent. Even though off-label use is widely accepted, it raises several legal questions, particularly with regard to the liability of the treating doctor and the pharmaceutical company marketing the drug.
Compassionate Use Programs
Compassionate use is the use of unauthorised (i.e., experimental) drugs in patients who are for a variety of reasons not eligible for a clinical trial. While introduced as early as 1987 in the United States, compassionate use is relatively new to EU law. It was first introduced in the 2007 EU regulation laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (Reg. (EC) No. 726/2004) (EMA Regulation). The EMA Regulation stipulates the conditions for compassionate use of drugs that are subject to centralised EU authorisation.
With respect to drug authorisations in national or coordinated authorisation procedures at Member State level, the Directive on Medicinal Products for Human Use, also referred to as the Community Code on Pharmaceuticals (Dir. 2001/83/EC), allows Member States to implement a reference to the requirements provided for in the EMA Regulation.
Based on the EU provisions, several Member States have introduced national compassionate use programs. Such programs are usually initiated by a pharmaceutical company and subject to regulatory requirements, some of which are defined in EU law. These requirements include, inter alia, the following:
- Compassionate use only applies to chronic or seriously debilitating diseases.
- No satisfactory treatment by an authorised drug is available.
- The respective drugs are provided free of charge.
For off-label and compassionate use, the Community Code provides a specific legal basis in case of emergencies, which enables Member States to allow marketing of drugs without approval and to relieve healthcare professionals and pharmaceutical companies of liability for unauthorised use. Member States have already made use of these provisions during the COVID-19 pandemic.
Scientific and Procedural Advice
EMA and the competent Member State drug authorities offer free scientific and procedural advice to companies and institutions developing drugs or vaccines against COVID-19. This includes regulatory advice in the development and marketing authorisation phases. The authorities are currently giving priority to projects related to the diagnosis and/or treatment of COVID-19.
Accelerated Procedure
In individual cases, EMA and national drug authorities offer an accelerated procedure for the authorisation of a drug or vaccine against COVID-19. This accelerated procedure includes the potential review of clinical data on a rolling basis, i.e., clinical data are submitted subsequently, and EMA reviews them as soon as they are made available. Likewise, some national drug authorities are currently accepting the successive submission of documents relevant for authorisation, in order to speed up the review proceedings.
PRIME Regime
In 2016, the Priority Medicines program (PRIME) was introduced as an opportunity for research-based pharmaceutical companies to make optimal use of the accelerated procedure. Drugs for which there is an unmet medical need are eligible for PRIME. To meet this criterion, a drug must either be used to treat a disease for which there is no treatment option available (as is the case with respect to COVID-19), or a drug must have a significant advantage over existing treatment options.
Expedited review under PRIME may take a maximum of 150 days (compared to the maximum of 210 days that the EMA may normally take to review the application documents), not including clock stops when additional documents are requested. Several drugs and vaccines intended to treat or prevent COVID-19 are currently passing through the PRIME procedure.
Conditional Marketing Authorisation
In exceptional cases, EMA grants provisional and conditional drug marketing authorisations, namely for drugs intended for the treatment, prevention or diagnosis of life-threatening or seriously debilitating diseases. Conditional marketing authorisation may also be considered for drugs intended for use against a threat to public health in a crisis situation identified by the World Health Organization or the European Union. The COVID-19 pandemic is likely to be the future textbook example of such a crisis situation.
The conditional marketing authorisation requires at least proof of a positive risk-benefit-ratio for the concerned drug. The authorisation is initially valid for one year, but can be extended or converted into an unconditional marketing authorisation after successful completion of all clinical trial phases. Since its introduction, the EMA has granted the conditional marketing authorisation in more than 30 cases, but not yet in connection with COVID-19.
Conclusion
Research companies and institutions should investigate at an early stage whether accelerated review and approval procedures or procedural support may apply to their ongoing and planned clinical studies in Europe and the United States. To successfully compete in the race to develop effective drugs and vaccines against COVID-19, companies and institutions need not only the right active ingredient, but also the right marketing authorisation and market access strategy.
