Industry review: Regulatory harmonization would enable robust and timely clinical development of vaccines

By Jane Byrne

- Last updated on GMT

© GettyImages/Volodymyr Horbovyy
© GettyImages/Volodymyr Horbovyy

Related tags Vaccine clinical trial application WHO

Convergence towards common global standards for clinical trial application (CTA) rules, along with unilateral and mutual recognition of CTA approvals are some suggestions made by industry insiders in a new paper to enable robust and timely development of vaccines.

Developing new vaccines is a complex process, they said.

"Vaccine developers and manufacturers are exploring technological advancements to translate breakthrough discoveries into novel vaccines which have the potential to provide protection from life-threatening and debilitating infectious diseases.

“[However] the benefits from these advancements will not be fully realized unless there is also significant progress in areas such as regulatory convergence and harmonization pertinent to clinical trials,” ​warn the four industry experts, based at Janssen Vaccines, Merck, Pfizer and GSK Vaccines.

Their paper, published in Vaccine,​ identifies several areas of potential improvement for transparency, clarity, and opportunities to leverage harmonization and regulatory reliance “to avoid wasting resources and time of all stakeholders.”

Commonly observed reasons for long vaccine approval timelines:

Slow review cycle     

The review cycle by the regulatory authorities and ethics bodies may be slow due to a lack of resources and expertise, which is compounded in multi-country clinical trials.

Multiplicity of approvals and sequential review  

Several ethics committee (EC) reviews are required, sometimes sequentially, which delays the timing for initiation of the regulatory review.

Interaction with ethics committees and health authorities          

Many countries do not allow interactions with ECs and national regulatory authorities (NRAs) prior to the submission of applications. Such pre-submission meetings could, however, provide a better understanding of the vaccine product, clinical protocol design, the development history and overall development plan and product specifics and add to the mutual understanding by the reviewing bodies and vaccine developers.

Genetically modified organism (GMO) regulations         

GMOs are often handled by different ministries without alignment regarding submission windows and approval timelines. Also, ministries in charge of overseeing GMOs often lack the knowledge about clinical trials with medicinal GMO products.

There is an urgent need for global bodies such as the World Health Organization (WHO) to partner with and national regulatory authorities (NRAs) to establish and implement a common, global set of requirements for clinical trial applications (CTAs) per phase of vaccine development, they stressed.

Clinical trial application process

All medicinal products, including vaccines, must go through three phases of development – each including sometimes multiple clinical trials – before the product can be licensed. For each of these trials, a separate CTA must be filed to the health authority in each of the participating countries and within some countries, also to additional regional or local authorities. In addition, multiple ethics and biosafety bodies – sometimes in a sequential process – are usually involved in the review of a study at each of the participating clinical study sites.

“The current divergence and lack of a coordinated approach to regulate CTAs may impede innovation, waste precious resources and ultimately slow down access to innovative vaccines.”

Since approvals for CTA applications can take up to a year, or sometimes even longer, and, given that for the development of a novel vaccine typically three development phases are needed, it can be followed that the delay in CTA approvals has a significant impact on the overall development timeline and leads to a delay to license that can possibly add up to three years, noted the authors.

“Considering that, for diseases such as HIV, Tuberculosis or Malaria, millions of healthy people get infected every year, even a 50% effective vaccine could prevent millions of healthy people getting infected every year and any unnecessary delay to having a vaccine approved entails a very concrete human cost.”

The solution 

To accelerate access to life saving vaccines, they outlined how a common, harmonized, global set of data requirements and review practices for CTAs as per the phase of development would help, through:

  • a guidance document issued by WHO or other unifying bodies
  • a one-dossier-fits-all template for CTA

The objective is to allow applicants to use a common dossier for applications to ECs and NRAs in different countries.

A coordinated and parallel application to ECs and NRAs could considerably shorten development timelines without impacting negatively on the overall quality of the review, they said.

Clear and transparent assessment timelines for approvals vary considerably between countries and regions and between ECs and NRAs.

“Having clear and transparent timelines and adherence to these will result in predictability for applicants and more efficiencies in the conduct of clinical studies.”

Transparency, consistency and predictability in regulatory outcomes and decision making is needed, continued the pharma stakeholders.

Pre-submission meetings with NRAs and ECs can help in the mutual understanding of CTAs, they said. The outcomes of the EC and NRAs’ reviews, as well as established timelines, should be shared in a transparent manner with the vaccine developers which will facilitate subsequent applications and reviews. “This will also contribute considerably towards building mutual trust, which is paramount to reliance.”

Unilateral and mutual recognition among regulators 

Closer harmonization and specialization of NRAs, where possible, can lead to reliance, unilateral recognition and potential mutual recognition, they believe.

Using converging guidelines and considering joint reviews between regulatory authorities or ethics committees is an efficient way forward, they reckon.

Given the complexities of modern clinical development, reliance and joint reviews will also allow certain committees and authorities to specialize in particular diseases or technologies without having to spread resources too widely to review every single application, they said.

“An interesting example of joint reviews of vaccine CTA applications is the one carried out by the African Vaccine Regulatory Forum (AVAREF), which was applied to the Ebola vaccine reviews.”

A harmonized approach to clinical trial applications will also benefit expedited procedures and approvals of CTAs during outbreaks and health emergencies (such as e.g. Ebola, SARS-CoV-2 outbreaks) or can accelerate the approval of clinical trials for products with a high unmet medical need which could benefit from more streamlined and expedited approval pathways, they added.

“These expedited pathways can not only provide potentially quicker access to certain vaccines but also to provide vaccine developers with insights early in the development, which in turn can inform the development in the right direction thus enabling greater efficiencies.”

Learnings from COVID-19

The authors noted that the experience of the regulatory landscape during the SARS-CoV-2 pandemic shows that it is possible to accelerate CTA approvals without impairing on the quality of the CTA review.

“It will be of importance to learn from the experience gained to initiate a discussion regarding the implementation of such measures into the standard processes also.”

Source: Vaccine 

Title: Regulatory harmonization and streamlining of clinical trial applications globally should lead to faster clinical development and earlier access to life-saving vaccines.


Authors: L Scheppler, N De Clercq, M McGoldrick, J Dias

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