Dr. Chitra Lele is Chief Scientific Officer, Sciformix Corporation.

Chitra Lele, PhD

Meeting today’s complex regulatory demands can be a challenge for even large pharmaceutical companies. But for the industry’s small and medium-sized organizations, it can seem impossible to keep updated on the requirements at all times and fulfill them to ensure compliance. That challenge is further compounded by increased financial constraints and pressures to get products to market as quickly as possible, with limited resources to move them through the pipeline.

	Typically, small and medium-sized companies outsource their clinical trials to full-service contract research organizations (CROs). However, as CROs are often selected for their niche patient recruitment capabilities, they may not always have the required level of skill across the drug development spectrum, in areas such as data management, statistical design and analysis, medical writing, safety, and regulatory submissions. 

	Furthermore, clinical trials are often outsourced to multiple CROs, across multiple geographies. This has become very common now, given that many small biotechnology companies are focusing on rare diseases or biologic products that target specific populations. This means that pharmacovigilance (PV) data, along with the technology infrastructure to support it, will also be housed at multiple CROs, with limited control over data standardization. 

	As a result, safety data may be analyzed, reported, and reviewed separately, rather than at the aggregate (product) level, which could distort the view of the data. This puts organizations at risk when filing new drug applications (NDAs) to obtain marketing authorization. During this time, it is important to review and analyze consolidated data, define the initial product label, and proactively identify and manage safety concerns. Even if a single service provider is used for all clinical development activities, that provider may not have the specialized expertise required for postmarketing safety assessment, which requires the processing of large volumes of spontaneous adverse event data and the necessary technology maturity to do so.

	Later in the process, when products are finally introduced to the market, it is not practical for small and medium-sized companies to employ end-to-end regulatory and safety and risk management teams in-house with the breadth and level of expertise required. Diverting their limited manpower away from the company’s core activities of product development and marketing is not viable. Organizations that do not have an established safety group typically place these responsibilities under clinical development or regulatory affairs, which can result in lack of focus on critical PV activities. 

	Additionally, clinical and regulatory activities in the post-approval phase for registration in different markets and evaluation of safety, efficacy and, effectiveness for subgroups and for other indications can also be quite resource-intensive. Hence, it is also challenging for small companies to ensure adequate focus across all critical areas following marketing approval.

	All the above-mentioned challenges have become very real of late, and require timely solutions. Outsourcing strategies employed by small and medium-sized companies tend to be the most efficient for their immediate needs and tend to be fit-for-purpose given their focus on rare diseases and products targeting specific population groups, but may not be best suited to provide the required focus on safety across the product lifecycle in times of increased regulatory expectations around product safety and benefit-risk evaluation.  

	In the clinical trial environment, in order to understand the safety profile of a product, evaluation of all safety data across multiple ongoing and completed clinical trials is necessary. Aggregating and reviewing this data in real-time is important in the context of the FDA’s guidance for investigational new drug (IND) safety reporting. Timely reporting ensures that the FDA is able to consider whether changes should be made to trial conduct, and also allows investigators to take any essential steps to protect subjects. 

	Establishing and maintaining all safety operations in-house is a challenge for small and medium-sized companies, as dedicated professionals are required to manage both safety operations as well as the underlying technology infrastructure. Implementing the necessary technology, with validated, regulatory-compliant safety systems, comes with a large investment in a robust quality management system and the expertise to support the solutions. Furthermore, this can be made more complex by the unpredictable nature of the safety workload. 

Even when safety operations are outsourced, the ownership squarely rests with the sponsor, as regulatory expectations are very clear around this. Maintaining in-house expertise to provide the appropriate level of oversight for the outsourced operations is also a major challenge for many small and medium-sized companies. 

	Similarly, safety operations such as aggregate safety reporting, benefit-risk evaluation, signal detection, and development and implementation of risk management plans are becoming more complex and resource-intensive. Across Europe and several other countries (including Australia, Canada, and Japan), specific regulatory mandates to have qualified persons responsible for PV (QPPV) and local
	individuals responsible for PV pose additional operational challenges to small and medium-sized companies. By outsourcing safety responsibilities during clinical trials and the post-approval phase to functional service providers (FSPs), small and medium-sized companies can balance their workload and ensure best practice operations. 

	A real-life case study of this included a US-based biotech company specializing in the characterization and process engineering of complex molecules. Given its size and focus, the company didn’t have in-house PV expertise and clinical safety was being handled by a partner pharma company. However, the relationship with their partner was being dissolved and the company had an immediate need for safety services to develop standardized operating procedures (SOPs) for individual case safety report (ICSR)-related activities. The FSP (Sciformix) developed an engagement plan, analyzed the client processes, created detailed work instructions, and prepared a safety management plan. After finalizing the processes with the client, a knowledge transfer training session was completed via the train-the-trainer model and a hybrid resourcing model was implemented for ICSR processing. The hybrid operational model consisted of a local medical reviewer/operations leader and offshore services from Asia. This enabled real-time support at an optimized cost. The following client benefits were achieved:

		Quick transition of services from the pharma partner to FSP.

		Cost-effective model for end-to-end PV support, including safety database hosting, ICSR management, aggregate reporting, regulatory intelligence, and audit and inspection support.

		Fast-track implementation of database and other PV services. 

		Sustainable ramp-up and capabilities, within short notice.

Product lifecycle safety and regulatory needs

	During the product lifecycle, there are a number of safety and regulatory activities that are critical to maintain, as shown in Figure 1, from pre-clinical development to Phase IV. These activities can all be fairly resource-intensive and many small and medium-sized companies are unable to prioritize them or have the expertise necessary to fulfill them internally. 

	Given the strict requirements of regulatory bodies, appropriate SOPs and safety management practices are essential in order to remain compliant. If safety regulations are not met, this can lead to high costs through missed work, rework, or financial penalties.

 Regulatory authorities such as the FDA and UK’s Medicines and Healthcare products Regulatory Agency (MHRA) issue warning letters for major regulatory violations observed during inspections. Consequences of the warning letters are serious (e.g., loss of trust by patients and healthcare professionals regarding company products; damaging effect on stock prices; negative impact on approval of future submissions). 

	The FDA’s enforcement actions can include clinical trial holds that could cause inordinate and disruptive delays in clinical development activities and timelines, product recall, seizure, injunction, administrative detention, and monetary penalties and/or prosecution.

The most common pitfalls in safety monitoring during the product lifecycle include failure to:

		Integrate multiple safety databases for comprehensive safety review.

		Develop robust written SOPs and work instructions for safety management.

		Analyze, review, and document all pertinent clinical safety data (adverse events and events of interest, laboratory data, and other investigations).

		Review and update investigator’s brochure (IB) on a timely basis.

		Coordinate case submissions to regulators, ethics committees, and investigator sites across multiple clinical studies, as required and within timelines.

		Submit development safety update report (DSUR)/IND annual reports per schedule and applicable regulations.

		Ensure audit and inspection readiness at all times.

	Similarly, design, analysis, and reporting of clinical trials may not be of the desired quality and may cause inordinate delays in submissions, even if the patient recruitment timelines are met. This would have serious resource implications for the smaller companies.

	With compliance and resource requirements in mind, organizations may consider outsourcing clinical, safety, and regulatory activities. Three drivers should be taken into consideration when contemplating this option: people, process, and technology. 

	For small and medium-sized companies, workforce constraints have significant impact on the cost and flexibility of their operations. External providers are able to deliver a flexible flow of qualified, competent, and specialized personnel. These staff, with deep expertise in safety, medical, clinical, biometrics, regulatory, and technology, can meet the quality standards expected for regulatory compliance and submissions. All of this is possible without the need for companies to themselves recruit, train, and retain dedicated staff. 

	Unpredictable workloads are a reality in PV, with valleys and spikes, especially for marketed products, meaning companies have to be prepared with options to handle these fluctuations (see Figure 2). Working with an outsourcing partner allows convenient access to a broader pool of staff within the outsourcing organization. Resources can be trained and deployed within weeks to manage the increased workload and can then be withdrawn as needed, providing flexible and cost-effective resourcing solutions for surge management. 

	As mentioned earlier, without well-defined SOPs and safety management practices, compliance to regulatory demands can be impossible. Yet establishing these practices can be expensive and resource-intensive. Specialty outsourcing providers are able to provide end-to-end solutions across clinical development, regulatory, and safety with robust and ready-to-go solutions. These processes can be individually tailored to the company’s products, processes, and requirements, eliminating time investment from in-house resources. Furthermore, outsourcing providers are able to update these processes regularly according to the technological advances and changes in regulatory requirements. 

	Technology is essential for clinical, safety, and risk management operations. Outsourcing vendors can provide tested and ready-to-go infrastructure, with knowledgeable and experienced staff to ensure high-quality systems. Utilizing a specialized vendor can also provide strong business continuity and disaster recovery plans.

	Such vendors can help build pragmatic and compliant systems to meet company requirements and provide well-defined quality management plans, robust service-level agreement (SLA) compliance frameworks and metrics, analytics, and reporting.

Specialized safety and regulatory solutions: Advantages and benefits

	“PV-in-a-Box” is a holistic model offered by Sciformix, bringing together safety, technology, and advisory services into a complete end-to-end PV solution (see Figure 3). 

	To ensure regulatory compliance, integrated and shared services are utilized, thus, allowing users to gain a full picture of the safety requirements while optimizing resource deployment. 

	Drilling down to the product level, PV-in-a-Box can enable quicker and more informed decision-making through real-time tracking of benefit-risk profiles to support the maintenance of safer medicines to the market. As part of the solution, an automated technology platform plays a key role by fostering collaboration between disparate teams, seamless processes, and effective analysis of data.

	Teams that specialize in market access strategies and have an understanding of the regulatory environment in various markets can advise on the submission requirements for regulatory approvals, especially in the semi-regulated or non-regulated markets. This specialized regulatory and clinical support increases the chances of successful clinical development programs-and the commercial success of the products. 

, PhD, is Chief Scientific Officer, Sciformix Corporation; email: chitra.lele@sciformix.com 

	1. Deloitte. Pharmacovigilance (PV) outsourcing – Emerging PV business models. 2014. 

https://www2.deloitte.com/content/dam/Deloitte/us/Documents/life-sciences-health-care/us-lshc-pharmacovigilance-outsourcing-021115.pdf 

	2. European Medicines Agency. Guideline on good Pharmacovigilance practices (GPV). 

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/08/WC500211728.pdf

	1. Narhi M, Nordstrom K, Manufacturing, regulatory and commercial challenges of biopharmaceuticals production: a Finnish perspective. 

European Journal of Pharmaceutics and Biopharmaceutics

. Volume 59, Issue 3, April 2005, pages 397-405. 

http://www.sciencedirect.com/science/article/pii/S0939641104002966 

	2. Regnstrom J, Koenig F, Aronsson B, Reimer T, Svendsen K, Tsigkos S, Flamion B, Eichler HG, Vamvakas S. Factors associated with success of market authorization applications for pharmaceutical drugs submitted to the European Medicines Agency. 

European Journal of Clinical Pharmacology

https://link.springer.com/article/10.1007/s00228-009-0756-y 

	3. Carrigan O P, A risky business: The detection of adverse drug reactions in clinical trials and post-marketing exercises. 

. Volume 55, Issue 3, August 2002, Pages 497-505. 

http://www.sciencedirect.com/science/article/pii/S0277953601001836 

	4. Gummerus A, Airaksinen M, Bengstrom M, Juppo A. Outsourcing of Regulatory Affairs Tasks in Pharmaceutical Companies-Why and What?

n. March 2016, Volume 11, Issue 1, pages 46-52. 

https://link.springer.com/article/10.1007/s12247-015-9235-4

	5. Aronson J. Post-marketing drug withdrawals: Pharmacovigilance success, regulatory problems. 

. Volume 72, issue 5, October 2017, pages 555-561. 

http://www.sciencedirect.com/science/article/pii/S0040595717300586

Articles

Meeting today’s complex regulatory demands when it comes to drug safety and pharmacovigilance can be especially challenging for small and medium-sized organizations. This report presents the benefits for these companies in outsourcing such activities to functional service providers (FSPs) during clinical trials and post-approval.  

Specialized Safety Needs for Small and Midsize Companies

Meeting today’s complex regulatory demands can be a challenge for even large pharmaceutical companies. But for the industry’s small-to-medium-sized enterprises (

), it can seem impossible to keep updated on the requirements at all times and fulfill them to ensure compliance. That challenge is further compounded by increased financial constraints and pressures to get products to market as quickly as possible, with limited resources to move them through the pipeline.

	Typically, SMEs outsource their clinical trials to full-service contract research organizations (CROs). However, as CROs are often selected for their niche patient recruitment capabilities, they may not always have the required level of skill across the drug development spectrum, in areas such as data management, statistical design and analysis, medical writing, safety, and regulatory submissions.

	Furthermore, clinical trials are often outsourced to multiple CROs, across multiple geographies. This has become very common now, given that many small biotechnology companies are focusing on rare diseases or biologic products that target specific populations. This means that pharmacovigilance (PV) data, along with the technology infrastructure to support it, will also be housed at multiple CROs, with limited control over data standardization. As a result, safety data may be analyzed, reported, and reviewed separately, rather than at the aggregate (product) level, which could distort the view of the data. This puts organizations at risk when filing new drug applications (NDAs) to obtain marketing authorization. During this time, it is important to review and analyze consolidated data, define the initial product label, and proactively identify and manage safety concerns. Even if a single service provider is used for all clinical development activities, that provider may not have the specialized expertise required for postmarketing safety assessment, which requires the processing of large volumes of spontaneous adverse event data and the necessary technology maturity to do so.

	Later in the process, when products are finally introduced to the market, it is not practical for SMEs to employ end-to-end regulatory and safety and risk management teams in-house with the breadth and level of expertise required. Diverting their limited manpower away from the company’s core activities of product development and marketing is not viable. Organizations that do not have an established safety group typically place these responsibilities under clinical development or regulatory affairs, which can result in lack of focus on critical PV activities. Additionally, clinical and regulatory activities in the post-approval phase for registration in different markets and evaluation of safety, efficacy and, effectiveness for subgroups and for other indications can also be quite resource-intensive. Hence, it is also challenging for small companies to ensure adequate focus across all critical areas following marketing approval.

	All the above-mentioned challenges have become very real of late, and require timely solutions. Outsourcing strategies employed by SMEs tend to be the most efficient for their immediate needs and tend to be fit-for-purpose given their focus on rare diseases and products targeting specific population groups, but may not be best suited to provide the required focus on safety across the product lifecycle in times of increased regulatory expectations around product safety and benefit-risk evaluation. 

	In the clinical trial environment, in order to understand the safety profile of a product, evaluation of all safety data across multiple ongoing and completed clinical trials is necessary. Aggregating and reviewing this data in real-time is important in the context of the FDA's guidance for investigational new drug (IND) safety reporting. Timely reporting ensures that the FDA is able to consider whether changes should be made to trial conduct, and also allows investigators to take any essential steps to protect subjects.

	Establishing and maintaining all safety operations in-house is a challenge for SMEs, as dedicated professionals are required to manage both safety operations as well as the underlying technology infrastructure. Implementing the necessary technology, with validated, regulatory-compliant safety systems, comes with a large investment in a robust quality management system and the expertise to support the solutions. Furthermore, this can be made more complex by the unpredictable nature of the safety workload. Even when safety operations are outsourced, the ownership squarely rests with the sponsor, as regulatory expectations are very clear around this. Maintaining in-house expertise to provide the appropriate level of oversight for the outsourced operations is also a major challenge for many SMEs.

	Similarly, safety operations such as aggregate safety reporting, benefit-risk evaluation, signal detection, and development and implementation of risk management plans are becoming more complex and resource-intensive. Across Europe and several other countries (including Australia, Canada, and Japan), specific regulatory mandates to have qualified persons responsible for PV (QPPV) and local individuals responsible for PV pose additional operational challenges to SMEs.

	By outsourcing safety responsibilities during clinical trials and the post-approval phase to functional service providers (FSPs), SMEs can balance their workload and ensure best-practice operations.

		Fast-track implementation of database and other PV services.

	During the product lifecycle, there are a number of safety and regulatory activities that are critical to maintain, as shown in Figure 1 below, from pre-clinical development to Phase IV. These activities can all be fairly resource-intensive and many SMEs are unable to prioritize them or have the expertise necessary to fulfill them internally.

 Regulatory authorities such as the FDA and UK’s Medicines and Healthcare products Regulatory Agency (MHRA) issue warning letters for major regulatory violations observed during inspections. Consequences of the warning letters are serious (e.g., loss of trust by patients and healthcare professionals regarding company products; damaging effect on stock prices; negative impact on approval of future submissions). The FDA’s enforcement actions can include clinical trial holds that could cause inordinate delays in clinical development, product recall, seizure, injunction, administrative detention, and monetary penalties and/or prosecution.

	The most common pitfalls in safety monitoring during the product lifecycle include failure to:

		Analyze, review and document all pertinent clinical safety data (adverse events and events of interest, laboratory data, and other investigations).

	With compliance and resource requirements in mind, organizations may consider outsourcing clinical, safety and regulatory activities. Three drivers should be taken into consideration when contemplating this option: people, process and technology.

	For SMEs, workforce constraints have significant impact on the cost and flexibility of their operations. External providers are able to deliver a flexible flow of qualified, competent, and specialized personnel. These staff, with deep expertise in safety, medical, clinical, biometrics, regulatory, and technology, can meet the quality standards expected for regulatory compliance and submissions. All of this is possible without the need for companies to themselves recruit, train, and retain dedicated staff.

	Unpredictable workloads are a reality in PV, with valleys and spikes, especially for marketed products, meaning companies have to be prepared with options to handle these fluctuations (see Figure 2 below). Working with an outsourcing partner allows convenient access to a broader pool of staff within the outsourcing organization. Resources can be trained and deployed within weeks to manage the increased workload and can then be withdrawn as needed, providing flexible and cost-effective resourcing solutions for surge management.

	As mentioned earlier, without well-defined SOPs and safety management practices, compliance to regulatory demands can be impossible. Yet establishing these practices can be expensive and resource-intensive. Specialty outsourcing providers are able to provide end-to-end solutions across clinical development, regulatory, and safety with robust and ready-to-go solutions. These processes can be individually tailored to the company’s products, processes, and requirements, eliminating time investment from in-house resources. Furthermore, outsourcing providers are able to update these processes regularly according to the technological advances and changes in regulatory requirements.

	“PV-in-a-Box” is a holistic model offered by Sciformix, bringing together safety, technology, and advisory services into a complete end-to-end PV solution (see Figure 3 below).

	To ensure regulatory compliance, integrated and shared services are utilized, thus, allowing users to gain a full picture of the safety requirements while optimizing resource deployment.

	Teams that specialize in market access strategies and have an understanding of the regulatory environment in various markets can advise on the submission requirements for regulatory approvals, especially in the semi-regulated or non-regulated markets. This specialized regulatory and clinical support increases the chances of successful clinical development programs-and the commercial success of the products.

PhD, is Chief Scientific Officer at Sciformix Corporation; email: 

https://www2.deloitte.com/content/dam/Deloitte/us/Documents/life-sciences-health-care/us-lshc-pharmacovigilance-outsourcing-021115.pdf

. Volume 59, Issue 3, April 2005, pages 397-405. 

http://www.sciencedirect.com/science/article/pii/S0939641104002966

	2. Regnstrom J, Koenig F, Aronsson B, Reimer T, Svendsen K, Tsigkos S, Flamion B, Eichler HG, Vamvakas S. Factors associated with success of market authorisation applications for pharmaceutical drugs submitted to the European Medicines Agency. 

https://link.springer.com/article/10.1007/s00228-009-0756-y

	3. Carrigan O P, A risky business: the detection of adverse drug reactions in clinical trials and post-marketing exercises. 

. Volume 55, Issue 3, August 2002, pages 497-505. 

http://www.sciencedirect.com/science/article/pii/S0277953601001836

	4. Gummerus A, Airaksinen M, Bengstrom M, Juppo A. Outsourcing of Regulatory Affairs Tasks in Pharmaceutical Companies-Why and What?. 

. March 2016, Volume 11, Issue 1, pages 46-52. 

Aronson J. Post-marketing drug withdrawals: Pharmacovigilance success, regulatory problems. 

 Volume 72, issue 5, October 2017, pages 555-561. 

Outsourcing safety responsibilities to functional service providers (FSPs) during clinical trials and post-approval can help small-to-medium-sized enterprises balance their workload and maintain best-practice operations. 

Chitra Lele, PhD

Articles

Specialized Safety Needs for Small and Midsize Companies

Specialized Safety and Regulatory Needs for Small and Medium Biopharma Companies