An Overview of Clinical Overview

Clinical Overview is a document presenting a critical analysis of Pharmacology, Efficacy, and Safety of the pharmaceutical agent. This document is developed for multiple objectives like product registration, justification for labeling document, and so on. A clinical overview helps the reviewer to understand the objective of the application and clinical development plan for a product in scope.

Raghu Rama Setty Alur, Freyr Solutions

AClinical Overview is an integrated document intended to provide critical analysis of Pharmacology, Efficacy and Safety of the pharmaceutical agent in humans. It is one of the important documents of Module 2 of the Common Technical Document (CTD) i.e., Module 2.5, which refers to the data provided in the comprehensive clinical summary, the individual clinical study reports presented in Module 5 and other relevant reports. It provides concise information about the conclusions and the implications of the clinical data provided in the dossier with a conclusive interpretation on the benefit-risk assessment of the medicinal product in scope.

The main sections of a Clinical Overview include product development rationale, overview of biopharmaceutics, overview of pharmacology, overview of efficacy, overview of safety, benefits and risks conclusions and applicable references. The CTD enables the customisation of the subsections based on the requirement, purpose of the clinical overview and the data available for the specific product in scope.

A Clinical Overview provides a brief discussion and interpretation of safety and efficacy findings related to

the product, along with other relevant information (e.g., pertinent animal data or product quality issues that may have clinical implications), based on the findings from the clinical studies and/ or published literature. Providing the strengths and limitations of the development program and study results help in analysing the benefits and risks of the medicinal product for its intended use. It serves as a reference to the overall clinical assessment of the product and supports the information provided in the prescribing information.

The Clinical Overview is developed for a variety of requirements in today’s scenario. Accordingly, there are two (2) types of Clinical Overviews: The Prospective and Retrospective Clinical Overviews. A Prospective Clinical Overview can be solely developed based on studies conducted by the innovator (for a new drug application to get the product registration) or data from studies conducted by the innovator and published literature data (for a hybrid application or 505b2 type of submissions, wherein the applicant rely on some of the safety and efficacy information derived from the Clinical Studies conducted by the Original Innovator) or solely developed by using data from published literature references (for Generic submissions or other submissions such as “Well Established Use” or “Bibliographic Submissions”). In all the above situations, the purpose of the Clinical Overview is to support the application as a part of marketing authorisation.

With regards to Retrospective Clinical Overview, this document is generally not submitted to regulatory agencies as a part of registration dossiers. However, it is developed as a substantiation/justification for the core labelling documents (e.g., Company Core Data Sheet (CCDS) or Company Core Safety Information (CCSI)) developed by the innovator, to have company’s standpoint on the information related to safety and efficacy of a particular medicinal product in scope.

When a Marketing Authorisation Holder (MAH) has multiple registrations for a product across the globe, the format and extent of content (volume and depth of information) of the product information available in each country’s labelling document vary significantly. This creates an ambiguity to consider what is the actual safety and efficacy information of the product in scope. In these situations, the MAHcan select one of the registered country’s labelling documents as Reference Safety Information (RSI) or create Core labelling documents (CCDS or CCSI).

In experience, most MAHs prefer to develop the core labelling documents to represent the Company’s standpoint on the safety and efficacy of a particular medicinal product by using all the relevant information already available with them for that product, hence the term used retrospective development. The process would not end by developing only core labelling documents, it is required to develop the justification or substantiation document for the information available in the core labelling documents. This is the beginning of the development of a retrospective Clinical Overview to have the evidence for the safety and efficacy information available in core labelling documents. This process is evolving and every time there is an update to core labelling documents (life cycle management), the Clinical Overview also needs to be updated to provide evidence to the changes made to core labelling documents.

The update to Core labelling documents can be either safety or non-safety related. The trigger to update can be internal or external. Internally driven changes are based on safety monitoring, resulted from post-marketing studies or post-authorization safety studies, and may be due to open signals,whereas the externally driven changes include the changes suggested by Regulatory Agencies. Whether the safety changes are internally driven or externally driven, post-validation of the changes, the update to core labelling documents, country labelling documents (in case of Agency driven) along with the justification document (Clinical Overview) is required. As the Clinical Overviews developed for internally driven or externally driven safety changes related to specific safety information and only safety section of the Clinical Overview needs to be developed, these are termed as Abbreviated Clinical Overviews.

Additionally, these simpler versions of the Clinical Overviews are developed and submitted to Regulatory agencies as a part of life cycle management activities and/or market extension for a particular medicinal product. These overviews are used to substantiate the labelling changes during the post-approval part of the medicinal product’s/drug’s life cycle. Apart from internally or externally triggered safety changes, these overviews can focus on the specific update to the labelling documents related to efficacy, pharmacology or any other information. These overviews are termed as Abbreviated Clinical Overviews (ACO), Addendum to Clinical Overviews (ACO), Tailored Clinical Overviews (TCO), Customised Clinical Overviews (CCO), etc., as these documents are confined to specific information updates related to

In a scenario where the Clinical Overview is developed entirely based on literature data (for generic or bibliographic or well-established use submissions), it is very important to consider the level or quality of evidence (hierarchy of evidence) to identify the literature articles.

the medicinal product. Although the terminologies may differ based on the company’s specific processes, the purpose it serves is the same.

Irrespective of the type of Clinical Overview and the time of its submission, the level of evidence is very important. When the Clinical Overview is developed solely based on the clinical studies conducted by the sponsor for a new chemical entity, it is the first consolidated document that talks about the product’s safety and efficacy. In this scenario, the Clinical Overview should reveal the strengths and limitations of the clinical development program and study output. It should also provide the benefits and risks of the product for the intended use.

When the Clinical Overview is developed for Hybrid applications or the evidence comes from both the studies conducted by the sponsor and the literature data, the purpose and development strategy of the Clinical Overview should be clearly presented to help the reviewer. Development of hybrid Clinical Overview may trigger by introducing some novelty to the existing approved product. This may be a change in indication, new indication, new dosage form, new strength, new route of administration, new combination, new presentation, new target population (introducing paediatric indication), etc. The pros and cons of the change must be mentioned with the available evidence.

In a scenario where the Clinical Overview is developed entirely based on literature data (for generic or bibliographic or well-established use submissions), it is very important to consider the level or quality of evidence (hierarchy of evidence) to identify the literature articles. It is recommended to take help from medically qualified personnel in this process. In general, the well-accepted quality of evidence can be presented based on preference as follows. • Clinical Practice Guidelines • Meta-analysis and/or Systematic reviews • Randomized Controlled Trials • Active Treatment Controlled Trials

• Placebo Controlled Trials • Uncontrolled Trials • Cohort Studies • Retrospective Studies • Case Series • Case Reports • Expert Opinions • Narrative Reviews • Editorials

In the cases where a lot of information is available, the literature with highquality evidence would be preferred to use to develop the Clinical Overview. It is acceptable to omit the lower level of evidence when a significant amount of data is available with a high level of evidence. Few other points to consider while identifying the information for Clinical Overview are the impact factor of the journal, relevance of the information, the objective of the article, statistical parameters used, results of the trials or meta-analysis, statistical significance, power of the study, subset of the population enrolled, efficacy or safety parameters used and precision of analytical methods used (but not limited to).

The information mentioned in each subsection of the clinical overview should be relevant to the subsection with the proper flow of the information. This helps the reviewer to understand your case and the objective of the document. Below is the information that can be covered in each subsection of the Clinical Overview.

Product Development Rationale section should provide the details on pharmacological class of the product, give details on the pathological conditions in which the product is intended to be used, describe the existing therapeutic options available for the current condition in scope, how the product in scope is superior with regards to safety and/or efficacy or improve the condition/ compliance (once daily versus multiple administrations, oral administration versus parenteral administrations,) etc. This section should also cover the clinical development programme with details like completed, ongoing and planned clinical studies and the basis for the application. A summary of the scientific advice received (if any) from the regulatory agency can be provided.

Overview of Biopharmaceutics should represent the critical analysis of the problems related to bioavailability or bioequivalence of the product that might directly or indirectly affect the safety or efficacy of the product in scope. In case of generic submissions with Bioequivalence studies are part of the submission, a summary on the bioequivalence parameters and how the marketed formulation is equivalent to reference products (90% confidence intervals for Cmax, AUC 0-t and AUC0inf) can be provided. If there is any study conducted to show the influence of food on the product’s rate and extent of absorption can be provided.

Overview of Pharmacology should cover the information related to Pharmacokinetics and Pharmacodynamics of the product.This section should address pharmacokinetics in healthy subjects, patients and special populations (paediatric, geriatric, pregnant women, lactating mothers, patients with renal impairment, patients with hepatic impairment, obese patients, cancer patients, patients with

A Clinical Overview provides a brief discussion and interpretation of safety and efficacy findings related to the product, along with other relevant information (e.g., pertinent animal data or product quality issues that may have clinical impli- cations), based on the findings from the clinical studies and/or published literature.

human immune deficiency virus, etc.). It also covers intrinsic factors (age, sex, race), extrinsic factors (diet differences, smoking, concomitant drugs) and pharmacokinetic interactions and their output. Details on rate and extent of absorption, distribution details, information related to metabolism and metabolites, excretion are included. With regards to pharmacodynamics, mechanism of action, receptor binding, onset of action, pharmacokinetics/pharmacodynamics relationships and pharmacodynamic interactions can be covered.

An overview of efficacy should provide the critical analysis of the efficacy of the product in intended use in the intended population. The analysis should cover the relevant data and should explain why and how the information supports the proposed use and the data in prescribing information. The quality of evidence should be considered and if there are any issues with efficacy parameters employed in the study or premature termination of the studies can be described with proper reasons. If there are any studies conducted in special populations, they should be clearly mentioned and if there are no studies conducted, support should be provided to extrapolate the efficacy data from the general population to the special population.

Overview of Safety should cover the critical analysis of the safety data with regards to adverse effects (details on common, nonserious and serious), warnings and precautions, drug interactions, safety in special populations, overdose and its management. The adverse events data should be provided in detail with relevant tabulations and frequency of the adverse events, nature of patient population and extent of exposure to be provided.

The benefits and risks conclusions section should provide the succinct, integrated and properly explained assessment of the product for the intended use. If multiple indications are proposed, the benefits and risks conclusions should be provided for each indication. This section should be developed based on the proper weighing of key benefits and the key risks without any ambiguity. Finally, a list of references used in developing the Clinical Overview to be listed.

AUTHOR BIO

Raghu Rama Setty Alur is a Pharmacologist with 16+ years of experience in Medical Writing, Clinical Research and Labeling. He has proven track record in developing the high-quality documents related to clinical, non-clinical and toxicological domains. He has few international publications to his credit. He has been part of Freyr for more than 5 years and currently heading the Medical Writing Department at Freyr. Raghu has successfully managed projects in the fields of clinical pharmacology, Medical Writing clinical and medical affairs, regulatory affairs, preclinical research, toxicology, and publication (Scientific) writing.

A brand of Darling Ingredients

Emirates SkyCargo

In the time of COVID

Julian Sutch

Manager Global Pharma Sales, Emirates SkyCargo

The year 2020 was shaped by the COVID-19 pandemic and pharma being at the forefront of efforts to combat the virus was vulnerable and also impacted by the lockdown. How did the pandemic impact EKSCand what steps did you take to deal with it?

The COVID-19 pandemic had a massive impact on the aviation and air cargo industry globally. As part of our normal business, we transport cargo on dedicated freighter aircraft and also in the bellyhold of our passenger flights. The latter plays quite a key role as prior to COVID-19, around 70 per cent of the total freight we transported were carried on passenger aircraft. When COVID-19 forced the complete suspension of passenger flight operations in late March, this entire capacity suddenly was no longer available to us and we were left only with operations on our 11 Boeing 777 freighter aircraft.

At this point of time, worldwide, there was still demand for the transportation of cargo. This covered goods that were urgently required by people across the world- PPE, medical equipment such as ventilators, pharmaceuticals as well as food items. Given the distributed nature of the global economy, these critical commodities needed to be transported from the markets where they had been produced to communities across the globe. And so, we had to innovate very quickly, almost reinvent our complete

business model overnight and ensure that we were fulfilling our social responsibility by transporting these urgently required commodities across the world.

Our main response was focused on two streams- streamlining our operations here at Dubai and making additional air capacity available to our customers for transport of essential goods through Dubai to the rest of the world.

As restrictions on international travel exposed frailties in supply chains & lockdowns, we could foresee a situation where there would no longer be adequate cargo capacity available in the market to transport essential supplies. How did you overcome such a situation?

Julian Sutch is commercially responsible for Emirates SkyCargo’s global pharmaceutical division having been appointed in August 2016. Julian has been in the logistics industry for nearly 15 years since university, spending 10 of those in freight forwarding in Dubai predominately setting up the Middle East regional distribution for GlaxoSmithKline and opening an Pharma hub facility for API in the Dubai Airport Freezone.

Our first order of business was to restore air cargo connectivity to markets around the world so that we could continue transporting essential commodities that were required in the response to COVID-19.

In order to do this, we started operating our Boeing 777-300ER passenger aircraft as cargo only aircraft. This had never been done before and our team had to work within a very short time to plan our new route network, work with our partners across the world and also work with the relevant authorities

to get the required permissions to operate the flight. Our Boeing 777-300ERs are widebody aircraft with around 40-50 tonnes of bellyhold capacity (without passengers).

We were able to deploy these and increase our destination network from about 35 (served by our 11 Boeing 777 freighters) at the end of March to around 50 by April. Over the next two months, we further increased our network to more than 75 destinations. Currently we’re flying to more than 130 destinations across six continents.

In the meantime, we also came up with other innovative solutions to increase the amount of air cargo capacity. This included loading cargo on the seats of passenger aircraft and in the overhead bins. Of course, before we introduced this, we also had to make a complete safety evaluation and develop guidelines for our worldwide team to follow. All this was done in an extremely short period of time as the market continues to evolve rapidly.

In the month of June, we also removed seats in Economy Class from 10 Boeing 777-300ER aircraft to convert them into what we like to call ‘minifreighters’. We now have 16 of these aircraft in our fleet to complement the air cargo capacity that we offer on our full freighters and passenger aircraft.

What innovative strategy did you come up with to bolster the cargo capacity?

We reacted quickly to changing circumstances and have endeavoured to maintain trade lanes across the world during these challenging times with our flights.

Our most important change to operations during the COVID-19 crisis was to operate our passenger aircraft as cargo only to maintain connectivity for essential goods including medical supplies, pharmaceutical cargo and food. Over one year, we operated more than 27,800 cargo only flights on passenger aircraft, transporting more than 100,000 tonnes of food and pharma on these flights.

We also operated a record number of charter flights as and when requests came in from our customers for transporting critical commodities. The investment in our modern aircraft fleet, infrastructure at our hub and development of processes, helped us stand the test and face extremely difficult market conditions.

In terms of our hub operations, in early April, we decided to consolidate all our cargo handling operations at Dubai International Airport (DXB) from our previous dual airport hub model with both DXB and DWC with the latter handling cargo transported on the Boeing 777 full freighter aircraft. Given the reduced number of passenger flights, we were able to streamline our processes with all flights taking off from DXB.

However, we have had a finger on the pulse of the market and started preparing very early on for the eventual transportation of COVID-19 vaccines. Since late 2020, we have been flying these much needed vaccines on our flights and so far we have transported more than 75 million doses of COVID-19 vaccines to more than 60 cities on 250 flights, mostly to developing countries. We have a dedicated GDP certified COVID-19 vaccine hub in Dubai and have also partnered with entities in Dubai and with international organisations such as UNICEF to be able to expedite the movement of COVID-19 vaccines through Dubai to developing countries.

Emirates Sky Cargo marks a year of PAX-freighter flights. What are some of the hurdles in operating a cargo-only flight as a passenger aircraft, and what factors do you attribute the success to?

Prior to the COVID-19 pandemic, no air cargo carrier including Emirates SkyCargo had operated a cargo only flight on a passenger aircraft. Passenger freighters came into play only because of the severe capacity crunch in the global market for the transport of urgently required PPE, medical equipment, pharmaceutical supplies and food.

Setting up passenger freighter operations on a global scale was a complete shift in our usual business model and this meant that our teams had to work from the ground up, getting approvals for flight operations from various authorities, drawing up a destination network and schedule based on demand for cargo in the various markets, evaluating and drawing up new operational safety guidelines and working closely with our ground handlers across the different markets we operate for any additional resources and equipment required for cargo loading/ offloading especially in cases where cargo is required to be loaded inside the aircraft cabin.

Over a period of one year from 16 March 2020, Emirates SkyCargo operated more than 27,800 cargo only flights on its fleet of widebody passenger aircraft. This was by far the most number of passenger freighter flights operated by a single carrier in the industry. We attribute our success to the fact that we have been agile and kept an open mind, working closely with our customers and responding quickly to the rapidly evolving market dynamics. Of course, none of our successes would be possible

without the support and hard work of our teams and our partners around the world.

How would EKSC’s partnership with UNICEF act as a blueprint for collective global partnership in the face of future health and humanitarian crises?

Emirates SkyCargo has over two decades of expertise in transporting pharmaceuticals, vaccines and other relief materials. We also have experience working with various international organisations to help deliver relief efforts. Over the years, we have deployed many charter flights on our Boeing 777F aircraft transporting aid and relief materials to areas impacted by humanitarian crises including natural disasters.

One of our strongest partners is the International Humanitarian City (IHC) located in Dubai who are the world’s largest humanitarian hub based in Dubai. Emirates SkyCargo has worked closely with IHC to operate humanitarian flights. In October 2020, we also signed an MoU with IHC to combine our mutual but complementary expertise to deploy relief efforts more rapidly and effectively across the world. The IHC are also one of our partner organisations in the Dubai Vaccine Logistics Alliance and our primary aim is to use our Dubai hub to rapidly distribute COVID19 vaccines from manufacturing locations to the rest of the world.We are also working with UNICEF to support the COVAX facility by expediting shipments of COVID-19 vaccines on our flights. So far, we have flown more than 75 million vaccines on our flights.

We feel that it is our social responsibility to use our expertise in logistics to help communities across the world stay connected to the goods they require.

What according to you is the greatest lesson learned from the COVID-19 pandemic, and what lasting effects do you foresee over the next 5–10 years?

If there is one lesson that COVID-19 has taught us it is that we must always stay on our feet. We cannot become complacent just because we have developed the best product or solution. The pandemic has demonstrated to us that even the most carefully laid out plans can be changed overnight. The only option is to work closely with our customers, continuously innovate and stay ahead of the game.

The aviation and air cargo industry are currently still coping with the effects of the pandemic. However, one thing that the pandemic has done is to encourage outside the box thinking. We have implemented measures that we thought were never possible before- such as operating cargo only flights on passenger aircraft or loading of cargo on the seats of the aircraft. The industry that emerges from the crisis will be much more responsive, agile and resilient in dealing with such worldwide disruptions.