COVID-19 and expedited approval of therapeutic goods – a global perspective

By Alison Choy Flannigan, Partner, Leader – Health & Community, Hall & Wilcox, Australia; James Fry, Partner and Head of Life Sciences, Mills & Reeve, UK; and Carolina M. Wirth, Of Counsel, Arnall Golden Gregory LLP

Coronavirus Disease 2019 (COVID-19) has significantly impacted the healthcare sector across the globe. There has been a rush to get medicines and medical devices (ie COVID-19 diagnostic test kits, drugs, face masks, ventilators, vaccines and digital thermometers) to clinical trials and to market.

Never before has there been such demand for urgent and practical therapeutic goods regulatory advice.

The various regulators around the globe (including the US Food and Drug Administration (FDA), the Therapeutic Goods Administration (TGA) in Australia, and the European Medicines Agency (EMA) (Government Agencies)) have been working very hard to facilitate and expedite clinical trials, market approvals and emergency use authorisations.

It is not only the product which is regulated, but also the method of manufacture, with the manufacturing required to comply with Good Manufacturing Practice (GMP).

What are the legal, regulatory and ethical issues of rushing medicines and medical devices to market, including safety, human rights and equity of access?

Typically, a pharmaceutical company needs many years to collect evidence that confirms the safety, quality and efficacy of a medicine by running clinical trials and doing other research.

There needs to be a balance between expediting making medical products available for COVID-19 and meeting safety and efficacy requirements. Sixty years ago, thalidomide, a drug that was prescribed to many pregnant women in order to relieve pregnancy nausea, was withdrawn from the market after thousands of mothers gave birth to disabled babies. More recently, Johnson & Johnson is facing numerous class action lawsuits in relation to vaginal mesh products, which are alleged to cause pain, bleeding, infection, organ perforation and autoimmune problems. Therefore, it is extremely important, for example, that any COVID-19 vaccine is beneficial and does not create greater harm than the disease it is used for.

Further, as we have seen in the past with HIV medications, and the competition for scarce resources such as ventilators in the US, equity of access is also an issue, particularly as patents grant monopoly rights.

It will be interesting to see what Governments will do in balancing the interest of the patent owner against public health and COVID-19.

'The tough question is going to be for the first tens of millions of doses, who should get it. Ideally it should not depend on the country that is manufacturing the vaccine,' said Soumya Swaminathan, chief scientist at the World Health Organization (WHO), in response to a question from Research Professional News.^[1]

What is involved with off-label use?

A therapeutic good is registered or listed by the relevant Government Agency for an approved use. A use outside the approved uses, 'off-label use', is not permitted unless an exception applies.

The benefit of using therapeutic goods which have been approved for one use for another novel purpose is that that good has already been assessed and approved by the relevant Government Agency and therefore the path to market is often faster.

For COVID-19, much has been said about the use of 'hydrochloroquine' and the related drug 'chloroquine' a drug normally used to treat malaria, as a possible treatment for COVID-19. The drug has been promoted by some world leaders, including US President Donald Trump, however, concerns have been raised about its safety and efficacy. While the US FDA issued an Emergency Use Authorisation (EUA) for the drug in March, it revoked the authorisation just a couple of months later after clinical trial data results showed that the drug may not be effective to treat COVID-19, and that the 'drug's potential benefits for such use do not outweigh its known and potential risks.'^[2]

What about clinical trials?

Clinical trials involve the trialling of novel drugs and medical devices and require Human Research Ethics (HREC) Approval and either registration by or notification to the relevant Government Agency.

There are typically four phases of clinical trials for medicines:

Phase I clinical trials are done to test a new biomedical intervention for the first time in a small group of people (eg 20-80) to evaluate safety (eg to determine a safe dosage range and identify side effects).

Phase II clinical trials are done to study an intervention in a larger group of people (several hundred) to determine efficacy (that is, whether it works as intended) and to further evaluate its safety.

Phase III studies are done to study the efficacy of an intervention in large groups of trial participants (from several hundred to several thousand) by comparing the intervention to other standard or experimental interventions (or to non-interventional standard care). Phase III studies are also used to monitor adverse effects and to collect information that will allow the intervention to be used safely.

Phase IV studies are done after an intervention has been marketed. These studies are designed to monitor the effectiveness of the approved intervention in the general population and to collect information about any adverse effects associated with widespread use over longer periods of time. They may also be used to investigate the potential use of the intervention in a different condition, or in combination with other therapies.

Typically sponsors do not charge patients for being included in a clinical trial so while a clinical trial is essential in obtaining data for sponsors, clinical trials are a means to an end for commercial pharmaceutical and medical device companies.

What are governments in the US, the European Union and Australia doing to fast track approval of therapeutic goods?

US

In the US, the FDA has employed numerous measures in order to make much needed therapeutic goods available to combat the COVID-19 pandemic, including, but not limited to:

1. Emergency Use Authorisations (EUAs) – allowing for the use of unapproved medical products such as tests and devices to diagnose, treat and prevent the spread of COVID-19;
2. exemptions and exclusion from certain requirements of the Drug Supply Chain Security Act; and
3. expedited development and assessments under the Coronavirus Treatment Acceleration Program (CTAP).

The FDA has issued EUAs for the use of medical devices such as ventilators, respirators, face masks and face shields, protective barrier enclosures and decontamination systems in healthcare settings. Manufacturers and stakeholders can submit a request to the FDA in order to have their medical devices added to the relevant EUA.

When it comes to drugs and biologics, the FDA is taking a more measured approach, recommending that potential sponsors submit a pre-Investigational New Drug Application (Pre-IND) meeting request to enable more timely initiation of clinical trials under an IND.^[3] According to the FDA, most investigational drugs or biologics will not meet the requirements for an EUA. As such, the FDA has not issued many EUAs for therapeutic drugs or biologics to treat or prevent COVID-19; however, to date, there are over 140 active clinical trials in the US.^[4]

EUAs have also been issued for the use of various COVID-19 diagnostic tools such as polymerase chain reaction (PCR) and antigen tests in authorised laboratories.^[5] Specifically, the FDA has issued EUAs to different types of COVID-19 tests:

• polymerase chain reaction (PCR) tests, a molecular diagnostic testing technique that detects the genetic material from the virus and can help diagnose an active COVID-19 infection;
• serological tests that look for antibodies to the virus, which can help identify individuals who have developed an adaptive immune response to the virus, as part of either an active infection or a prior infection (serological, or antibody, tests should not be used to diagnose active infection); and
• the newest type of authorised COVID-19 tests are antigen tests, designed for the rapid detection of proteins from the virus that causes COVID-19.^[6]

The declaration of a public health emergency triggered statutory exemptions for ‘covered COVID-19 products’ from the product tracing and identification requirements of the Drug Supply Chain Security Act (DSCSA). The DSCSA outlines critical steps to build an electronic, interoperable system to identify and trace prescription drugs as they are distributed in the United States. For the exemptions to apply, the distribution of the products must be triggered by an emergency 'transaction' during the COVID-19 public health emergency.^[7] This has helped expedite the availability of necessary treatments during the pandemic.

The FDA established the Coronavirus Treatment Acceleration Program (CTAP) in order to facilitate the development and availability of potential COVID-19 treatments. The program prioritises drug and biological therapy proposals with strong scientific merit by:^[8]

(a) Connecting developers and scientists seeking to develop or evaluate new drug and biological therapies with the right FDA staff to possibly expedite clinical studies. With a first wave of requests behind them, the FDA will generally respond within a day.

(b) Providing ultra-rapid, interactive input on most development plans. Interactions have generally been prioritised based on a product’s scientific merits, stage of development, and identification as a possible priority product in consensus United States Government documents.

(c) Providing ultra-rapid protocol review – within 24 hours of submission, in some cases.

(d) Completing the review of single patient expanded access requests around-the-clock – and generally within three hours.

(e) Working closely with applicants and other regulatory agencies to expedite quality assessments for products to treat COVID-19 patients and to transfer manufacturing to alternative or new sites to avoid supply disruption.

European Union

Medicines and vaccines

The European Union (EU) has implemented a comprehensive programme in response to the COVID-19 crisis. Special procedures are currently available to support the rapid development of safe and effective vaccines and therapeutics.

The European Medicines Agency (the EMA) has adapted its procedures in order to shorten the regulatory timelines by accelerating every stage of the regulatory pathway. However, there remains a strong emphasis on ensuring that applications are supported by robust and sound scientific evidence.

The rapid procedures stem from the EMA's emerging health threats plan. A grouping of scientific experts drawn from around the EU regulatory network – the COVID-19 EMA Task Force (COVID-ETF) – is focusing on the review of COVID-19 therapeutics in co-ordination with the human medicines committee (CHMP).

Special accelerated mechanisms tailored for the current crisis are on offer, prioritising the most relevant proposals. These mechanisms include:

• rapid scientific advice for developers of medicinal products. This will provide guidance on the best methods and study designs to generate robust data in support of an application for authorisation, as well as on manufacturing and control processes. Medicines intended to tackle COVID-19 will received additional support in the form of a waiver of fees for scientific advice and a significant reduction of the timescale to 20 days.
• shortened timetables for the review of paediatric investigation plans (PIPs) to 20 days. In addition, a four-day period is offered for checking that an applicant has complied with the agreed measures in a PIP before a marketing authorisation can be submitted.

Once an application for a marketing authorisation has been submitted, an accelerated review process is available. The normal timeline for the evaluation of an application is up to 210 days, but this is being significantly reduced to meet the urgent need to address the pandemic. Targeted measures include:

• rolling review of data for promising medicines as they are generated, rather than as a complete package at the date of submission. Several rolling reviews can be carried out as new data emerge, with submission of a formal application once the data is considered to be complete.
• where the rolling review is not available or not chosen, accelerated assessment of the marketing authorisation application. This can reduce the maximum review time substantially from the maximum 210 day period to 150 days, with shorter timescales likely in practice.

The repurposing of previously authorised products for the treatment or prevention of COVID-19 may benefit from these support measures. This is important as many existing medicines are considered for their usefulness in fighting the pandemic, and may offer a faster path to clinical rollout.

There is also the option of making unauthorised medicines available at national level through compassionate use programmes. While these fall within the responsibility of member states, the EMA can enable coordination of a common approach through the CHMP.

The EMA is working internationally both through the International Coalition of Medicines Regulatory Authorities (ICMRA), and bilaterally with the US FDA, to provide a coordinated response and reduce friction between different systems.

Refer to: https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/covid-19-whats-new

Medical devices

Medical equipment and devices are primarily regulated at national level. A coordinated system of CE-marking by bodies designated by individual EU member states applies, with varying degrees of clinical investigation required for different types of device.

Some EU-level interventions are in place. For example, emergency legislation to control the export of personal protective equipment (PPE), was introduced on a temporary basis to maintain supplies within the EU. Waivers of customs duties and value-added tax (VAT) on certain kinds of imported medical equipment have been applied.

The EU was to have introduced a completely new medical devices regime from 26 May 2020. This legal change has been suspended for one year to avoid the imposition of unnecessary burden on both regulators and producers while they focus on combating the virus. While the delay makes sense in terms of focusing efforts during the current crisis, many device producers will already have taken steps to adhere to the new system and may not therefore realise much benefit.

During the pandemic, EU member states are implementing their own programmes, within the overall system, to ensure availability of necessary equipment.

In the UK, clinical investigations of devices that will have a direct impact on the COVID-19 emergency will benefit from a fast-track review process. Particularly important equipment, such as ventilators, PPE and testing kits, may be able to benefit from special exemptions from the normal regulatory approval process.

Refer to:

https://ec.europa.eu/growth/sectors/medical-devices_en

https://www.gov.uk/government/collections/mhra-guidance-on-coronavirus-covid-19

Australia

In Australia, the Government has introduced a number of measures to get therapeutic goods to market sooner including:

1. time limited exemptions – including for medical device PPE, COVID-19 tests to accredited laboratories and domestically manufactured ventilators;
2. expedited assessments – prioritising and expediting assessments; and
3. an expedited recall pathway – recalls can be expedited within 24 hours.

The Therapeutic Goods Administration (TGA) has been working with the Australian Border Force and Intelligence to monitor compliance.

The TGA is currently undertaking an expedited assessment process for all medical devices associated with the detection, prevention and treatment of COVID-19. All applications in relation to COVID-19 are being expedited as a matter of priority, separate to the Priority Review pathway. Technical files and data for assessment must be submitted.

The Australian Government has expedited premarket approval of new ventilator devices and allowed off-market use and modifications to ventilators, anaesthesia gas machines and other devices intended for respiratory support, in response to the COVID-19 pandemic. Although inclusion on the Australian Register of Therapeutic Goods (ARTG) is required for a medical device to be lawfully supplied, the TGA has taken a proactive stance with the repurposing of alternative devices (such as veterinary devices and the rapid establishment of new manufacturing capacity).

The Therapeutic Goods (Medical Devices—Ventilators (COVID-19 Emergency) Exemption 2020 has been passed to enable manufacture in accordance with stated specifications.

In response to the COVID-19 pandemic, the TGA has expedited the approval (with conditions) of COVID-19 tests including tests intended for laboratory use and those intended for use by specified health professionals at the point of care (POC).

Overseas approval does not mean automatic approval in Australia, however the TGA has entered into various international agreements and arrangements with other countries and regulatory authorities to support international regulatory collaboration. Some of these agreements and arrangements allow us to use inspections conducted by these regulatory authorities as part of the Good Manufacturing Practice (GMP) clearance process in lieu of the TGA performing its own on-site inspection.

1. FDA – The Australian TGA does have a cooperation agreement with the US FDA. The TGA will accept evidence from the US FDA for GMP clearance applications using the Compliance Verification (CV) pathway, irrespective of the country the inspection is performed in, as long as the inspection was performed using a comparable GMP standard.
2. European Directorate for the Quality of Medicines (EDQM) – The EDQM inspects manufacturers of active pharmaceutical ingredients (APIs) and excipients outside the European Union (EU), based on its own program. In most cases this involves the participation of an EU regulatory authority. The EU regulatory authority issues a GMP certificate following a successful on-site inspection and uploads it to the EudraGMDP database. For the CV pathway, the TGA will only accept the GMP certificate issued by an EU regulatory authority that also has a Mutual Recognition Agreement (MRA) or equivalent with Australia, together with the corresponding EDQM inspection report.

Usually when using an FDA or EU Certification, bridging documentation is required to explain the difference and reconcile compliance with the Australian standards.

Refer to: https://www.tga.gov.au/how-we-regulate/manufacturing/manufacture-medicine/good-manufacturing-practice-gmp/international-agreements-and-arrangements-gmp-clearance

[1] https://www.researchprofessionalnews.com/rr-news-world-2020-4-push-for-equity-of-access-to-covid-19-vaccines/
[2][2] See FDA’s ‘Letter revoking authorization for emergency use of chloroquine phosphate and hydroxychloroquine sulfate’, available at https://www.fda.gov/media/138945/download
[3] https://www.fda.gov/media/137927/download
[4] https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap
[5] https://www.fda.gov/media/136702/download
[6]  Id.
[7] https://www.fda.gov/regulatory-information/search-fda-guidance-documents/exemption-and-exclusion-certain-requirements-drug-supply-chain-security-act-during-covid-19-public
[8] https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap