The Aggregate Safety Assessment Plan A valuable tool for clinical trial safety planning

THE AGGREGATE SAFETY ASSESSMENT PLAN

A valuable tool for clinical trial safety planning

The Drug Information Association / American Statistical Association Interdisciplinary Safety Evaluation working group has proposed an Aggregate Safety Assessment Plan (ASAP). The ASAP promotes a consistent approach to safety data collection and analyses across studies. The ASAP is a valuable tool for sponsors to enhance characterisation of the emerging product safety profile.

Barbara A Hendrickson, Immunology Therapeutic Area Head, Pharmacovigilance and Patient Safety, AbbVie

Recently, a Drug Information Association / American Statistical Association-sponsored Interdisciplinary Safety Evaluation working group published a recommended approach to the aggregate assessment of clinical trial safety data. The proposed Aggregate Safety Assessment Plan (ASAP) has several components including identification of the safety topics of interest, how the safety data will

be pooled across clinical studies and the data analysis standards that will be employed. In addition, the ASAP delineates how the safety data will be reviewed in aggregate to enable earlier signal detection as well as to promote consistent messaging regarding the emerging safety profile of the product. Lastly, the ASAP prompts a clinical trial sponsor to consider what key gaps in safety knowledge will remain at the time of product filing and potentially require further data collection or safety studies. The ASAP is an internal document compiled by a clinical trial sponsor early in the investigation of a product. The ASAP is meant to be a ‘living’ document that evolves over the different phases of clinical development. At a minimum, clinical scientists familiar with the product and disease under study in conjunction with safety scientists and statisticians with expertise in the analysis of safety data should collaborate on the creation of the ASAP. Ideally, the ASAP effort should also be supported by an epidemiologist. This team starts by reviewing what is known about the mechanism of action of the product, pre-clinical study results, drug-related adverse events reported in early human studies and, if applicable, available safety information from related products. This information, coupled with knowledge about the epidemiology of the study population (such as associated co-morbidities), forms the basis for the selection of the safety topics of interest. The safety topics of interest require collection and analysis of data beyond that which is routine for a clinical study. Creation of an ASAP should prompt team members to consider questions about the safety topics of interest that will be posed by regulatory authorities, healthcare providers and patients. These questions drive decisions about the data, which will be needed at regulatory submission. In addition, team members should research how the safety topics of interest have been assessed in the past by other clinical trial sponsors. Pre-emptive and thoughtful aggregate safety evaluation is critical in order to thoroughly characterise a product’s safety profile and important product risks.

Why should company management invest more resources earlier into safety assessment?

A comprehensive understanding of the safety data from completed and ongoing clinical trials is critical to understanding the benefit: risk profile of a product. A common objection to devoting resources to more in-depth safety planning earlier is doubt about whether a product will progress into later stages of development. However, formation of an ASAP may improve efficiency by serving as the reference point for the safety standards used in individual study statistical analysis plans. In addition, a proactive dialogue regarding the statistical outputs needed by the clinical team for documents such as the Investigator Brochure or Development Safety Update Report can minimise the need for ad hoc requests and missed timelines. Lastly, even if a programme does not advance into late-stage development, the learning gained from populating an ASAP is carried over to work on the next project which may be successful.

In addition, over the past 10 years, health authority expectations have risen regarding the quality of clinical trial safety data. As more therapies become available for specific diseases, the focus progressively shifts to how the safety of various products is differentiated. Product approvals may be denied or delayed due to safety concerns or an uncertain benefit: risk profile for the drug doses studied in the pivotal trials. Moreover, a lack of safety planning may lead to less favourable labelling than anticipated. Consequently, devoting resources to the characterisation of a product’s ‘safety story’ is just as important as to its ‘efficacy story’.

Nonetheless, clinical trial sponsors may not concentrate closely on the safety package until after the registrational studies have started. The dangers of this approach are important missing data, challenges in data integration due to lack of standardisation across studies, and concerns arising about the adequacy

of the safety data. For example, regulatory authorities may expect expert adjudication of designated adverse events or request specific statistical analyses, both of which may not have been considered or planned before the start of the clinical trials. Once the pivotal studies have begun, the case report forms would have been finalised and the initial patients enrolled. At that point, a course correction of the study can be problematic and costly. In addition, often there is a lack of foresight as to how the safety information will be put into the appropriate context at the time of product submission. For instance, the observation of certain adverse events during the clinical studies may raise concerns, particularly if there is a higher number of events in the active drug treatment group versus the control arm. While such an imbalance may be a chance occurrence, without information about the event background rate in the study population, this possibility cannot be assessed. An example is the surprisingly increased incidence of melanoma in patients with Parkinson’s Disease (PD). Although the underlying basis for this finding is not clear, a mutation or other alteration in a gene or protein conferring an increased risk for both PD and melanoma is possible. Knowing this association between PD and melanoma is critical to understanding an observation of a higher than anticipated rate of melanoma in PD clinical trials.

How does the ASAP facilitate ongoing safety monitoring and signal detection?

While the evaluation of individual case reports remains valuable, regulatory authorities increasingly are focused on the monitoring of clinical trial safety data in aggregate. A single case report can be informative for an adverse event that is typically drug related, temporally associated with experimental product administration and for which there is no clear alternative etiology (e.g., anaphylactic reaction occurring less than 30 minutes after ingestion of a product with no other cause identified). However, aggregate data assessment is needed for adverse events which are anticipated to occur in the patient population regardless of study participation (e.g. stroke in patients with osteoarthritis). For these events, noting that individual subjects have risk factors for the occurrence of an event is insufficient justification for a lack of association with product administration. Instead, the frequency, nature and severity of similar event reports in patients receiving the drug requires scrutiny. The ASAP has a section which is devoted to the description of the methodology for monitoring of aggregate safety data from the ongoing clinical trials, including potentially still blinded studies. Such assessments can support investigational new drug safety reporting decisions. Without a systematic approach to continual safety evaluation, signals may escape early detection and a sponsor could be surprised with an unanticipated safety concern at study completion.

The proposed Aggregate Safety Assessment Plan (ASAP) has several components including identification of the safety topics of interest, how the safety data will be pooled across clinical studies and the data analysis standards that will be employed.

How does the ASAP help a sponsor recognise key safety knowledge gaps?

One of the other sections of the ASAP prompts the clinical trial sponsor to consider what key questions about the safety profile of the product will remain unanswered at the time of regulatory submission. The cross-functional team also should be cognisant of the queries from healthcare professionals and patients regarding the safety of the product. More information may be needed regarding the frequency of the event, including in selected patient subpopulations, as well as the adverse event’s range of severity, reversibility and risk factors for occurrence. Another critical question may be how effective proposed measures are in mitigating the risk of an adverse effect of the product. By considering what will be important missing information at product filing, the clinical trial sponsor can proactively plan for how these knowledge gaps will be addressed either in an additional study or sub-study or through postmarketing safety surveillance.

How does the ASAP support the safety messaging for a product?

Another valuable aspect of the ASAP is the foundation set for consistent safety messaging. Throughout a product’s lifecycle, communications regarding safety data occur to both internal and external stakeholders. Safety information is transmitted externally to regulatory authorities, clinical trial investigators and participants and more generally via public disclosures such as press releases, meeting presentations and publications. To help direct these communications, the ASAP refers to the concept of a “safety storyboard” which could be a slide deck or a written document. The safety storyboard changes in content over the course of clinical development. Initially the emphasis is on the

preclinical safety results and first in human study conclusions. Later as more clinical trial data accumulates, identified risks may emerge for which there is sufficient data to conclude a causal association with product administration. In addition, available data should be described relevant to potential risks for which there is a basis to suspect a link with product use. Other safety topics of interest may also warrant documentation of agreed upon conclusions based on current data. Examples include events of higher regulatory or prescriber interest based on the epidemiology of the patient population (e.g., major cardiovascular events in diabetes) or traditional safety concerns (e.g., drug induced liver injury). In addition, if risk minimisation measures are recommended for certain identified and potential risks, these actions should be part of the key safety messages. The safety storyboard can serve as the source of aligned safety messages which guide communications to various safety stakeholders.

Summary

The ASAP puts a clinical trial sponsor in a better position to detect safety risks earlier and to optimally support the benefit:risk profile of the product at submission and in communications to various internal and external stakeholders.

References

Hendrickson, B.A., Wang, W., Ball, G., et al. (2021) Aggregate Safety Assessment Planning for the Drug Development LifeCycle. Therapeutic Innovation & Regulatory Science. 55(4): 717-732.

Bose, A., Petsko, G.A., and Eliezer D.(2018) Parkinson’s Disease and Melanoma: Co-occurrence and Mechanisms. Journal of Parkinson’s Disease 8:385-398.

Barbara Hendrickson is the Immunology Therapeutic Area Head in Pharmacovigilance and Patient Safety at AbbVie. She is a subspecialist in Pediatric Infectious Diseases and has 18 years of pharmaceutical and clinical trial experience. Dr. Hendrickson also coleads the DIA-ASA Aggregate Safety Assessment Planning Task Force.

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IMCD

A global leader in speciality chemicals and ingredients

Over recent years, IMCD has strengthened its position as a global leader in the distribution of specialty chemicals and ingredients. IMCD is committed to creating solutions that meet the demands of healthcare and product development. Paul Mimnagh, APAC Regional Director at IMCD, talks about the company’s post-covid strategy, missions for 2022, and the future of IMCD in the APAC region.

Paul Mimnagh, Business Group Director Pharmaceuticals, Asia Pacific

1) Can you begin by introducing IMCD and the business principles guiding the company?

The IMCD Group is a global leader in the formulation, sales and distribution of speciality chemicals and ingredients. As the Pharmaceuticals Business Group, our goal is to advance ideas for a healthy future. We seek to achieve this by co-creating with our customers and partners in the development and manufacture of today’s and tomorrow’s medicines. IMCD focuses on meeting the needs of all stages of healthcare development, from fine chemical synthesis or upstream development of APIs, to the formulation and manufacture of the final dosage form.

2) Can you outline IMCD’s footprint in the region and the areas of its global portfolio you are currently prioritising?

Globally, IMCD has around 300 technical sales experts who are experienced and professionally trained to understand the needs of our industry. Our network of Pharma Technical Centres (PTCs) underpins their ability to support our customers in delivering their medicines meaningfully. Our teams are focused on innovation, sustainability, and providing the best customer solutions.

Asia is the youngest of our global regions. But in a short period, it has grown to be our largest, with over 100 sales professionals and four Capitalise PTCs. We are channelling investment into ensuring the highest calibre of professionals in each country, supported by a matrix of sub-sector specialists and technical product managers.

We are adapted to the nuanced needs of each country, but critically, as a company, we have a team of regional experts covering the key subsectors of

our industry to support each local team in the APAC region, with a sharpened focus and understanding of the regulated synthesis, API, topical/ dermal, nutraceutical, and biopharma markets.

3) Speaking about products and therapeutic areas, how has IMCD’s portfolio evolved and where are you investing?

IMCD has long been a world leader in excipient distribution and this remains a core element of our business today and in the future. The APAC region closely follows IMCD’s global trend, and in line with global developments, has been focusing on strengthening our presence in APIs, nutraceuticals, and biopharma in recent years. The acquisitions of DCS, Signet, Whawon and Megasetia, provide our APAC business with a world-class portfolio, regional strength in these key territories, and of vast importance — an infrastructure of exceptional compliance and regulatory support in the field of APIs.

APIs are core to a successful portfolio, and as we strengthen our position here, we further increase our portfolio’s relevance to our customers. Additionally, the continuing expansion of our pharma technical network allows us a more robust geographic coverage and capabilities across the network, particularly in tablet coating, nutraceutical concept development, and API testing and formulation.

Our next focus is further expansion in biopharma, novel drug delivery, and analytical capabilities to better support our customers in generic and novel drug formulation.

4) Can you briefly explain the impact of COVID-19 on the company’s business and production?

As a speciality distributor, our first responsibility is to deliver quality ingredients to our customers. Our investment and focus on technical capabilities never overlook that absolute priority. This has never been more tested than during the COVID pandemic of the last two years. Early in the pandemic, we saw a massive surge in demand across our portfolio, from basic ingredients for over-the-counter medicines, to crucial APIs such as muscle relaxants for the process of intubation. We were able to draw upon global inventories and our leveraged positions with suppliers and providers to help many of our clients with critical supply issues.

In terms of market focus, the COVID-19 pandemic has been the biggest challenge and focus for the biopharmaceutical industry in 2020. Innovative solutions have been developed in diagnosis, treatment, and vaccination. Among these solutions, monoclonal antibodies are considered promising to treat people in intensive care.

When it comes to vaccines, billions of dollars are being invested into development and improvement. Vaccines are being produced with well-known technology like mRNA, but we’re also seeing interest in protein-based vaccines or viral vectors.

IMCD’s partners invest in capacity and portfolio extension to ensure the security of supply of those critical raw materials to the market. IMCD in turn provides essential services in logistics to make the supply chain robust, efficient, and available at the point of need.

5) What is IMCD’s approach in creating opportunities through technical expertise and experience to the APAC pharma manufacturing community?

Globally, IMCD has a network of seven PTCs. Under the coordination of the Cologne headquarters, these Technical Centres deliver on the following areas: training and development of our team, studying and understanding our suppliers' ingredients in challenging formulations, assisting our customers in developing their formulations, and in the development of novel concepts and formulations.

By successfully harnessing IMCD’s and our partners' knowledge with these capabilities, we equip ourselves to meet our customers' requirements, whether that is a simple need to source an ingredient, or our being intrinsically involved in developing new product ideas with our customers.

Specifically in APAC, we have four PTCs in Mumbai, Shanghai and two in South East Asia. Each PTC carries a fundamental responsibility to meet the service needs of customers in all aspects of Oral Solid Dosage Forms (OSDF) and dermal technologies. Additionally, each of our PTCs is an integral cog in a co-ordinated network. Each centre focuses on a particular area of expertise, topical dermal, controlled release, tablet coating, reverse engineering for our clients in the generic field.

6) How is IMCD’s APAC network expanding through organic growth, global relationships, and strategic acquisitions?

Since our first pharma greenfield sales operations in India and China in 2010, we have grown organically in doubledigit figures every year. The key to our success is organic growth, so organic growth remains our team’s first point of focus irrespective of what developments and successes we have.

We have expanded across the region with our key global partners. This expansion is based on our delivery of differentiated channels to the market, reflecting the wide diaspora of market dynamics and customer needs within Asia.

Strategic acquisition is also a major part of our development in APAC. In the last three years, we have closed several acquisitions, building our pharma positions in Vietnam, China, India, Korea and Indonesia. Of particular importance to our business were the acquisitions of Signet India, Megasetia Indonesia and Whawon in Korea. In each of these three cases, we have partnered with leading pharma distributors in their respective markets. In addition to strengthening our position in these markets, these acquisitions also bring new degrees of expertise in our target growth markets and high degrees of experience and learning in fine-tuning our customer intimacy in APAC.

As we look to the immediate future, IMCD will focus heavily on the continued expansion of our position through all three of these channels, with particular focus on the vast scope and potential for us to grow in China, Japan, Thailand, and Vietnam while also looking to strengthen our specialist positions in APIs, nutraceuticals and biopharmaceuticals.

To truly offer value and expertise in this sector, IMCD has to add new areas of expertise to our team.

7) Can you elaborate on IMCD’s capturing approach to emerging trends such as biopharma and wellness through nutraceuticals?

The biopharmaceuticals market is the fastest growing sector in the pharma industry today, with a CAGR of 7.32 per cent over the forecast period, 2021-2026. The market is driven mainly by the growing geriatric population, rising chronic diseases, and increasing acceptance of and huge market demand for biopharmaceuticals. The ability of biopharmaceutical products to address previously untreatable conditions has introduced innovative drugs in the market. An accelerating focus on research and related investments facilitates the massive demand for biopharmaceuticals.

In the biopharma field, IMCD's strategy is based on the fact that while our partners invest in capacity and portfolio extension, IMCD has to provide essential services in logistics to make the supply chain robust and efficient. In addition to growing into this vibrant sector with our principal partners, we seek to expand our portfolio to new and innovative partners, and technologies, focusing on offering products for upstream, downstream, and final formulations. These include low endotoxin carbohydrates, amino acids and polyols. Additionally, IMCD has dedicated our resources to mapping this market and targeting key players, CMOs, CDMOs, CROs, and universities.

To truly offer value and expertise in this sector, IMCD has to add new areas of expertise to our team. In 2021, we added several biopharma experts to our team, driving our coordinated global effort in this area. We will further expand our team with investment in biopharma experts in the APAC market.

With respect to nutraceuticals, APAC is a region where cultural diversity results in a wide range of consumer demands for nutraceutical end products. This is a complex challenge, but we see that the markets in Asia Pacific are very connected.

Our most recent APAC-wide campaign covered multiple segments within the broad and growing cognitive health category. Nutrition Business Journal states that consumers concerned about brain health far outweighs category sales. A significant health concern in the market surrounds the much-publicised mental health crisis resulting from the lockdowns and restrictions. IMCD has delivered innovative product concepts

that cover nootropics (focus), cognitive decline, and stress and mood.

An example of one of our recent innovations is Ginkgosome™. This is a fully-formed liposomal complex developed by IMCD’s internal herbal extract business, Network Nutrition. Two clinical trials demonstrate increased absorption with sustained release, maximising the health benefits of Ginkgo biloba in an easy and convenient one-a-day dose.

8) IMCD made headlines last year by joining forces with Megasetia. How does this fit into your longterm strategy?

Over the years in EMEA, we have refined the formula of how we offer true value to our customers, based on combining in-depth knowledge of the pharma industry needs with an intimate understanding of the local needs of our customers.

Our partnership with Megasetia, just like Whawon and Signet, accelerates our objectives to deliver the same knowledge and local understanding in APAC. Each of these companies surpasses all the others in their markets in technical support, market intelligence, and, most importantly, customer intimacy.

9) How does IMCD support its customers to overcome the challenges?

We have built a broad portfolio of pharmaceutical ingredients with the industry’s leading suppliers in terms of quality and innovation, as well as a strong infrastructure of technical and formulation capabilities. We have built a global team of best-in-class pharma experts who have access to industry-leading training academies.

When we successfully integrate and deploy these resources, we are equipped to support any challenges that they encounter.

Later this year, IMCD is launching our next phase of the digital platform providing secured access to our pharma solutions. This is an exciting step into our digital journey, which we look forward to sharing with you in the months ahead.

10) Looking towards the future, how do you expect the market to evolve in the coming years?

In the coming years, we should see a greater emphasis on segmented patient drug delivery tethered to the regulatory constraints around ingredient use. After the FDA announced its pilot program to review novel excipients, we will see novel excipients back on the agenda. As an engine for supply to the USA market, the APAC region needs to stay clear on its objectives. As such, IMCD needs to ensure the availability of regulatory, technical, and innovative input to our customers.

‘Traditional’ dosage forms still dominate in manufacturing, but orodispersible line extension, topical, and nasal/ oral spray delivery dosage forms will show much more growth potential than in previous years.

The old topics of improving bioavailability are only going to increase in importance, improving the potency of drug product performance can result in lower doses being required. There will be more emphasis on delivering drugs based on personalised medicine.

Last but not least, sustainability. This is a growing area of concern in corporate responsibility, but also in many consumer's minds. This is especially true when you consider the ultimate goal of personalised medicine is disease prevention, rather than traditional diagnosis and treat/cure.

We will see more ‘collaboration’ between medicine segment types such as prescription medicine for acute or medium-term chronic conditions, followed by symptom or side effect management and reduction and ending up with longer-term prevention of occurrence or recurrence. There are many exciting pathways to look at, and the APAC markets are a compelling ground for product development.

11) Is there a final message you would like to share with our international audience on IMCD APAC?

Our pharma business is just over 10 years old in APAC, but our growth has surpassed even our expectations. We have an increasing toolbox of digital and technical tools, a rapidly-expanding portfolio, and a business network spanning the globe. But the key element to IMCD’s success is our people. We are rightfully proud of our team's diversity, which draws from a range of backgrounds and nationalities, and enables us to benefit from fresh perspectives and ways of problem-solving. They engender a free and entrepreneurial spirit that breeds success for IMCD, our customers and partners.

Paul Mimnagh joined IMCD as International Product Manager in 2006, managing the pharmaceutical excipients portfolio through the IMCD sales network and developing the IMCD pharmaceutical business in emerging markets. He took up the role of Regional Director for Pharmaceuticals APAC in 2016 to drive IMCD’s expansion into the APAC market as the leading distributor of speciality pharmaceutical raw materials, to develop and implement regional business development and strategy to uncover new opportunities.

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