Expedited Approvals of Medicinal Products
Author:
Dr Leticia Monjas-Gómez
Consultant
Introduction.
Developing a novel drug, including discovery, nonclinical toxicology studies, and clinical studies, may take many years. Once a Company has generated this comprehensive body of data, the final step prior to regulatory approval is Health Authority review of the marketing authorisation application.
Review by regulatory authorities to evaluate whether the data support a positive benefit/risk profile takes many months, adding additional time before patients may access approved therapy. Here, we discuss the opportunities that the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA) offer in the US, the EU and the UK to expedite the regulatory approval timelines for drugs intended to treat serious diseases and unmet medical needs.
Accelerated Approval (US) and Conditional Approval (EU and UK) are options for applicants to provide preliminary data to Health Authorities in order to support a more limited approval. These pathways are generally reserved for diseases that despite having a significant impact on morbidity and/or mortality are sorely lacking in adequate treatment options, and may be proposed by either the Sponsor or the Health Authority. Additional data are then required to convert these approvals to “full approval.” If additional data do not in fact confirm the earlier promise of benefit, approval may be withdrawn. In addition, in the EU and in the UK, the Exceptional Circumstances approval pathway is available for those applications where it would not be possible or ethical to collect the standard level of evidence typically required to support approval.
Although not an approval pathway, the FDA can use its Emergency Use Authorization (EUA) authority to allow the use of unapproved medical products, or unapproved uses of approved medical products, to diagnose, treat, or prevent serious or life-threatening diseases when certain criteria are met, including that there are no adequate, approved, and available alternatives. Before the FDA can issue an EUA, the US Department of Health and Human Services (HHS) Secretary must make a declaration of an emergency, or a significant potential for an emergency and/or threat, justifying authorization of emergency use for a product.
US Accelerated Approval.
The accelerated approval provisions of the Food and Drug Administration Safety and Innovation Act (FDASIA) in section 506(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) provide that FDA may grant accelerated approval to “a product for a serious or life-threatening disease or condition…upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.”
Therefore, the two types of endpoints that can be used as a basis for accelerated approval are:
A surrogate endpoint that is considered reasonably likely to predict clinical benefit. A surrogate endpoint used for accelerated approval is a marker - a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit.
An intermediate clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit.
A clinical benefit is a positive therapeutic effect that is clinically meaningful in the context of a given disease. The clinical benefit must be weighed against a treatment’s risks to determine whether there is an overall benefit for patients (i.e., a positive benefit-risk profile).
The accelerated approval regulations state that accelerated approval is available only for drugs that provide a meaningful therapeutic benefit over existing treatments. FDA generally considers available therapy as a therapy that i) is approved or licensed in the US for the same indication being considered for the new drug, and ii) is relevant to current US standard of care for the indication.
The accelerated approval pathway, which was introduced in 1992, has been used primarily in settings in which the disease course is long and an extended period of time would be required to measure the intended clinical benefit of a drug. For example, accelerated approval has been used extensively in the approval of drugs to treat a variety of cancers and human immunodeficiency virus (HIV) disease where an effect on tumour growth or viral load can be assessed rapidly, but demonstrating an effect on survival or morbidity generally requires lengthy and sometimes large trials because of the duration of the typical disease course. Accelerated approval is also potentially useful in acute disease settings where the intended clinical benefit can be demonstrated only in a very large study because the clinical event that would need to be evaluated to demonstrate clinical benefit occurs rarely. For example, accelerated approval could be used for an acute condition where an effect on a surrogate endpoint could be shown in a small number of patients, but a much larger study would be needed to show the effect on a clinical outcome, such as survival.
FDA encourages sponsors to communicate with the Agency early in development concerning the potential eligibility of a drug for accelerated approval, proposed surrogate endpoints or intermediate clinical endpoints, clinical trial designs, and planning and conduct of confirmatory trials. The FDA bases its decision on whether to accept the proposed surrogate or intermediate clinical endpoint on the scientific support for that endpoint. Studies that demonstrate a drug’s effect on a surrogate or intermediate clinical endpoint must be “adequate and well controlled” as required by the FD&C Act.
Drugs granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval. For safety, the standard is having sufficient information to determine whether the drug is safe for use under conditions prescribed, recommended, or suggested in the proposed labelling. For effectiveness, the standard is substantial evidence based on adequate and well-controlled clinical investigations.
Under accelerated approval, FDA can rely on a particular kind of evidence, such as a drug’s effect on a surrogate endpoint as mentioned above, as a basis for approval. FDA carefully evaluates such evidence to ensure that any remaining doubts about the relationship of the effect on the surrogate to clinical benefit are resolved by additional post-approval studies. These post-marketing confirmatory trials have been required to verify and describe the anticipated effect on IMM or other clinical benefit. Where confirmatory trials verify clinical benefit, FDA will generally terminate the requirement. Approval of a drug may be withdrawn or the labelled indication of the drug changed if trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug (e.g., show a significantly smaller magnitude or duration of benefit than was anticipated based on the observed effect on the surrogate).
EU Conditional Marketing Authorisation.
The EMA offers a pathway enabling approval based on a more limited data set for new medicines that have the potential to address unmet medical needs. ‘Unmet medical needs’ means a condition for which there exists no satisfactory method of diagnosis, prevention or treatment authorised in the EU or, even if such a method exists, in relation to which the medicinal product concerned will be of major therapeutic advantage to those affected.
In the interest of public health, applicants may be granted a conditional marketing authorisation for such medicines on less comprehensive clinical data than normally required, where the benefit of immediate availability of the medicine outweighs the risk inherent in the fact that additional data are still required.
Medicines for human use are eligible if they are intended for treating, preventing or diagnosing seriously debilitating or life-threatening diseases. This includes orphan medicines. Its use is also intended for a public health emergency (e.g., a pandemic).
Conditional marketing authorization was introduced in the EU in 2006. The legal basis is Article 14-a of Regulation (EC) No 726/2004. The provisions for granting a conditional marketing authorisation are further elaborated in Regulation (EC) No 507/2006.
EMA’s Committee for Medicinal Products for Human Use (CHMP) may grant a conditional marketing authorisation for a medicine if it finds that all of the following criteria are met:
the benefit-risk balance of the medicine is positive;
it is likely that the applicant will be able to provide comprehensive data post-authorisation;
the medicine fulfils an unmet medical need; and
the benefit of the medicine’s immediate availability to patients is greater than the risk inherent in the fact that additional data are still required.
The CHMP encourages applicants to seek Scientific Advice to discuss a potential conditional approval strategy, and either the applicant or the EMA may suggest pursuing conditional approval. Although conditional approval is predicated on the applicant providing a more limited clinical data package, the CHMP generally expects a comprehensive chemistry manufacturing and control (CMC) and nonclinical data package to support the application, except possibly in the assessment of a product to be used in an emergency situation. Despite earlier approval, it guarantees that the medicine meets rigorous EU standards for quality, safety and efficacy and that comprehensive data is still generated post-approval. In contrast to the accelerated approval pathway in the US, conditional approval is not necessarily predicated on a surrogate endpoint.
Once a conditional marketing authorisation has been granted, the marketing authorisation holder must fulfil specific obligations within defined timelines.
These obligations could include completing ongoing or new studies or collecting additional data to confirm the medicine’s benefit-risk balance remains positive. EMA publishes the conditions of the marketing authorisation in the medicine’s European public assessment report (EPAR).
Conditional marketing authorisations are valid for one year and can be renewed annually. The marketing authorisation can be converted into a standard marketing authorisation (no longer subject to specific obligations) once the marketing authorisation holder fulfils the obligations imposed and the complete data confirm that the medicine’s benefits continue to outweigh its risks. Initially, this is valid for 5 years. It can then be renewed for unlimited validity. According to a report published by the EMA detailing Conditional Approvals from 2006–2016, Conditional Approvals are converted, on average, within 4 years.
As for any medicine, if new data show that the medicine’s benefits no longer outweigh its risks, EMA can take regulatory action, such as suspending or revoking the marketing authorisation. EMA can also take regulatory action if the company does not comply with the imposed obligations.
EU Marketing Authorisation under Exceptional Circumstances.
EMA may also grant a marketing authorisation in absence of comprehensive data under exceptional circumstances. Unlike conditional marketing authorisation, where marketing approval is granted in the likelihood that the sponsor will provide such data within an agreed timeframe, EMA can grant authorisation under exceptional circumstances when comprehensive data cannot be obtained even after authorisation. This authorisation route normally does not lead to a standard marketing authorisation.
Exceptional circumstances was introduced in the EU in 2004. The legal basis for the marketing authorisation under exceptional circumstances is the Article 14 (8) of the Regulation (EC) No 726/2004, and the relevant documentation for applications are laid down in Part II of Annex I of Directive 2001/83/EC, as amended.
Exceptional circumstances is granted for products for which the applicant can demonstrate that they are unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because:
the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence, or
in the present state of scientific knowledge, comprehensive information cannot be provided, or
it would be contrary to generally accepted principles of medical ethics to collect such information.
Consequently, the authorisation under exceptional circumstances is granted subject to a requirement for the applicant to introduce specific procedures, in particular concerning the safety of the medicinal product, notification to the competent authorities of any incident relating to its use, and action to be taken.
As early as possible during drug development, the applicant is encouraged to seek scientific advice from the EMA about the justification for applying for a marketing authorisation under exceptional circumstances, especially on the inability to provide comprehensive data. Any further discussion on the appropriateness should preferably occur in the context of the pre-submission meeting.
It should be noted that designated orphan products are eligible for approval under exceptional circumstances only if the criteria considered for the approval under exceptional circumstances are fulfilled.
A marketing authorisation under exceptional circumstances should not be granted when a conditional marketing authorisation is more appropriate. A conditional marketing authorisation is for example granted in the absence of comprehensive clinical data when it is likely that the applicant will be in the position to provide such data in a short timeframe, whereas the fulfilment of any specific procedures/obligations imposed as part of the marketing authorisation under exceptional circumstances is aimed at the provision of information on the safe and effective use of the product and will normally not lead to the completion of a full dossier.
The specific procedures/obligations that have been implemented and fulfilled by the applicant form the basis of a CHMP annual reassessment of the benefit/risk profile. Continuation of the authorisation should be linked to the annual reassessment of these conditions.
The renewal of the marketing authorisation of a medicinal product under exceptional circumstances follows the same rules as a “normal” marketing authorisation.
After five years, the marketing authorisation will then be renewed under exceptional circumstances for an unlimited period, unless the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal.
Differences between Conditional Authorisation and Exceptional Circumstances Marketing Authorisation
UK Conditional Marketing Authorisation and Exceptional Circumstances Marketing Authorisations.
The MHRA introduced a national conditional marketing authorisation and exceptional circumstances marketing authorisation for new medicinal products in Great Britain effective on 1 January 2021. Great Britain is England, Wales and Scotland. In Northern Ireland marketing authorisation applications for products which fall within the mandatory scope of the Centrally Authorised Procedure as laid down in Regulation (EC) No 726/2004, must be submitted to the EMA.
The schemes have the same eligibility criteria as the EU schemes and is intended for medicinal products that fulfil an unmet medical need. The designation of a product as being eligible for a conditional approval or exceptional circumstances scheme by the EMA or another jurisdiction may be taken into account by the MHRA, but the final decision on eligibility of the product for the Great Britain scheme will rest with MHRA.
US Emergency Use Authorization.
Although not an approval pathway, in the US there is a mechanism to facilitate the availability and use of medical countermeasures (MCMs) during public health emergencies: the Emergency Use Authorization (EUA). MCMs include drugs (e.g., antivirals and antidotes), biological products (e.g., vaccines, blood products, and biological therapeutics), and devices (e.g., in vitro diagnostics and personal protective equipment).
Before FDA may issue an EUA, the US Department of Health and Human Services (HHS) Secretary must declare that circumstances exist justifying the authorization (section 564(b)(1)). Under an EUA, FDA may allow the use of unapproved medical products, or unapproved uses of approved medical products in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions when certain statutory criteria have been met, including that there are no adequate, approved, and available alternatives.
Taking into consideration input from the FDA, manufacturers decide whether and when to submit an EUA request to FDA. Once submitted, FDA will evaluate an EUA request and determine whether the relevant statutory criteria are met, taking into account the totality of the scientific evidence about the product (e.g., vaccine) that is available to FDA. FDA usually calls Advisory Committee meetings for input. Advisory committees provide independent expert advice to the FDA on broad scientific topics or on certain products to help the agency make sound decisions based on the available science. Advisory committees make non-binding recommendations to the FDA, which generally follows the recommendations but is not legally bound to do so. During the COVID-19 pandemic, all vaccines went through the Advisory Committee process.
Summary & Conclusions.
Under specific circumstances, the US and EU/UK regulatory pathways allow applicants to submit limited data to support a drug approval, with the expectation that complete data will be subsequently provided to support a regular approval (accelerated approval in the US and conditional marketing authorisation in the EU and the UK). However, the EU and the UK provide one pathway for approval of drugs without what is usually considered “complete” data: exceptional circumstances (see Overview in Table below).
It is important to note that these expedited pathways are not intended to lower the bar for approval; instead, they enable Health Authorities to partner with applicants to generate the most relevant data and allow Health Authorities to prioritize review of applications for drugs that may be transformative for patients with serious conditions. One of the most important items when considering expedited approval programs is to engage in discussions with Health Authorities early to increase the probability of success. There are synergies that can be developed to be able to meet the requirements of multiple agencies and ensure early availability for patients in need of new therapeutic interventions.
