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Safety First

Published on 22/09/09 at 08:00am

A series of high-profile drug withdrawals in recent years has brought safety concerns to the fore, prompting more rigorous monitoring requirements from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA).

Many of the new initiatives - which include the creation of a clinical trials databank, systems for the collection of adverse events, and increasing use of post-marketing surveillance as a condition of drug approval - are designed to ensure that medications are monitored for their safety and effectiveness over the long-term and across wide populations.

How are companies responding to the new safety imperatives at a time when they are already facing some of their biggest challenges? ICON, a global provider of outsourced development services to the pharmaceutical, biotechology and medical devices industries, commissioned IMS Health to undertake a programme of research to address several key questions:

* What does the tougher safety environment mean for pharmaceutical operations?

* How is the industry preparing for closer scrutiny of its products pre- and post-approval?

* Is there sufficient resident expertise to meet the new demands of the FDA and EMEA?

IMS interviewed 140 senior industry executives responsible for pharmacovigilance, drug safety, and clinical research activities, drawn from a cross-section of top-tier and mid-sized pharmaceutical organisations, as well as biotech companies, in the US and eight EU countries. Most interviewees were leaders in pharmacovigilance or drug safety with global responsibility (see Appendix for full explanation of study methodology and respondents' profile).

The study was conducted in Q1 2009. The results of the research, which are summarised in this report, reveal a number of key findings:

1. Pharmaceutical and biotechnology companies feel it is right for them to accept more responsibility for drug safety at every stage of drug development. However, perceptions of the new regulations and their impact differ across segments of the industry:

* A majority of respondents report an appreciable impact on industry operations

* There are perceived disparities between the acknowledged importance of safety issues across the organisation

* The regulations are already affecting clinical development procedures to a greater or lesser extent, with a particularly notable impact on big pharma and biotech companies

2. Complying with the new regulations is challenging many organisations:

* Safety-related functions highlight a need for additional resources to support the management of new compliance measures.This need is greatest for regulatory departments in the next six months; and for medical and commercial in the next year

* There are acknowledged gaps in perceived expertise to deal with the new requirements

* Growing demand by regulators for real-world data will see increasing investment in patient registries or observational trials to support drug safety surveillance and monitoring in the industry

* Patient registries, or observational trials, will play a much greater role in regulators' demands and companies' plans

Few events in the business of pharma or biotech are as potentially damaging as a product withdrawal. It is debatable whether any in recent times have fuelled more public concern and disquiet than the removal of at least 10 high-profile brands from the market (or from impending launch) since 2005,due to concerns over safety. Collectively, these actions have likely cost the industry billions of dollars a year in lost revenue.

Impact of new regulations on development

Every product withdrawal tells a different story; each case has its mitigating factors. Indeed many events can play their part in potentially compromising safety: errors in diagnosis; inappropriate use; poor compliance with treatment.

Changing demographics and the ageing population will only add to this complexity, with increased requirement for multiple medications and higher potential for drug interactions in already susceptible patients.

Lessons have no doubt been learned from the past, and industry, regulators, health professionals, and patients must all continue to bear responsibility for ensuring the delivery of safe and effective care. But the overwhelming impression when things go awry is the same: there are certain shortcomings in current practice - be they scientific, regulatory, procedural, clinical, pre-or post-launch - that call into question the safety of marketed treatments.

Regulators raise the bar

Against this background, regulatory bodies - specifically the FDA and EMEA - have been quick to step in with tighter controls over the drug development process and tougher post-marketing scrutiny of product performance. Increasingly, they are focusing their efforts on more formal methods of monitoring drug use and outcomes after launch, to surface issues that can remain undetected in a clinical trial before a drug is exposed to a broad population in real-world clinical practice.

Among the most recent initiatives are:

* Provision in the FDA Amendments Act of 2007 (FDAAA) for the creation of a national clinical trials databank, and on May 22, 2008 launch of the "Sentinel Initiative" to track the performance and safety of marketed medical products and amass information on adverse events

* Increasing requests by the FDA and the EMEA for completion of a formal post-marketing surveillance programme as a condition of product approval. This is already standard practice in Japan, where companies must submit a "drug use investigation" plan as part of their regulatory submission

* An ambitious agenda launched by the European Risk Management Strategy (ERMS) in 2007 to protect the public's health, notably via more proactive pharmacovigilance

* Pan-European guidelines prepared by the EMEA emphasising the importance of post-marketing reporting systems. Many EU Member States are using long-term registries to comply with pharmacovigilance requirements and support reimbursement decisions

An appropriate direction

Just over half of the individuals who were interviewed (52%) for the research programme believed the primary trigger of recent regulatory revisions is the spate of drugs withdrawn from the market over the last few years - especially those in wide use or destined for large populations.

This view was most pronounced within biotechnology companies, where 72% of respondents highlighted product withdrawals as the underlying driver of regulatory changes.

In the main, participants regarded tighter regulations as appropriate: almost 60% were of the view that it was right for the industry to accept more responsibility for drug safety at every stage of drug development. It would seem that the new regulations are indeed having an impact on the way that clinical trials are now being conducted: companies are re-evaluating both design and methodology with an eye to improving study robustness and tightening safety controls. More than half (55%) of those surveyed confirmed that their companies are constantly updating their internal, standard operating procedures (SOPs) to conform to the new requirements.

Adapting to the new standards necessarily affects the work of all individuals in the development side of the business. In particular, it was considered likely to mean increased workloads for the medical and regulatory departments: a majority of participants predicted that this increase would be "considerable" for both departments.

Regulations making their mark

Three-quarters (77%) of individuals who were interviewed believed that the industry as a whole will be acutely affected by the new regulations. Interestingly, only 44% acknowledged a similar degree of impact within their own company - a difference that may be attributable to a form of respondent bias where individuals rate their own performance/knowledge above that of others. Nonetheless, the perceived effect on the industry was high.

More meaningful, however, is the breakdown in views by type of company. About half of the individuals from large companies and biotechnology firms said the new regulations have affected their clinical development process either to some or a great extent. This was far more substantial than the impact expressed by mid-sized companies.

Interviewees from regulatory (71%) and medical departments (73%) felt they had a good grasp of the regulations and their impact on the clinical development and commercialisation processes. However, only 45% of these same respondents attributed a comparable level of understanding to their sales and marketing colleagues.

Notwithstanding an element of response bias, since the voice of the commercial team was not directly heard, this is nevertheless an interesting perception from those who are most heavily involved in drug safety. It may or may not reflect an underlying plea for sales and marketing colleagues to acknowledge the growing importance of ongoing safety assessments. Approximately half of the respondents in big pharma and biotechnology companies felt the new regulations will have a meaningful impact on their clinical trial procedures compared to just a third of respondents in mid-sized pharmaceutical firms. This raises several questions:

* Do mid-sized companies shy away from high-risk therapy areas? Does a sometimes narrower focus mean the impact is less acute? Or are these companies already more cautious, more aware, or more self-contained entities?

Resource crunch in the making

Alongside the new regulatory standards comes a need for increased investment in safety monitoring expertise across the organisation - either internally or via external partners. This was considered most urgent for regulatory departments, with more than 50 percent of interviewees stipulating a need for additional resources in the next six months. Meanwhile, 80% felt that increased resources would be required in the medical department during the next 12 months, and 70% that the commercial arm would need resource support in the same timeframe. Recognition of the need to gear up - and quickly - applied across all three areas.

When asked whether regulatory, medical and commercial had the necessary in-house expertise (as opposed to manpower) to deliver on the new safety requirements, respondents were fairly confident in their abilities, while acknowledging gaps in all three areas: 21% suggested a need for supplementary experience in regulatory, 26% for medical and 41% for the commercial arm of the business.

Patient registries gaining traction

There is growing recognition among pharmaceutical and biotechnology firms of the need to invest in observational trials or "patient registries" to gather data on the use and effectiveness of medicines once they are on the market. The larger organisations and biotechnology companies appear to be taking the lead in stepping up their Phase IV activities in the near future: 69% of the surveyed biotechnology companies, 57% of the big pharma companies, and 35% of mid-sized companies indicated that they will devote more resources to post-marketing studies in the next five years.

The value of patient registries in monitoring drug safety at all stages of the clinical trial process was not widely recognised: 40% of respondents believed that registries were primarily a tool for amassing information once a drug has been approved.

In conclusion

Greater transparency around drug safety, signalled in the US by the appointment of Dr Margaret Hamburg as the new commissioner of the FDA remains a global regulatory and political priority. Tighter standards for safety reporting and surveillance herald a much tougher environment ahead.

Faced with new and increasing pressure on the drug development process, the industry is demonstrating its continued commitment to ensuring drug safety for in- development and on-market molecules. As yet, the full implications of regulatory changes for clinical development and resource investment are unclear. Understanding in the early phases of drug conception whether or not a drug will have undesired effects in a wider population remains a key goal.

Going forward, many companies will be focusing their efforts on shoring up their expertise and resources in order to meet the new requirements. As clinical activity increasingly shifts to regions such as Eastern Europe and the Asia Pacific, outsourcing safety processes may be one option for easing current constraints. This may be particularly relevant for biotechnology companies where global in-house capabilities may not yet have reached the level found in larger pharmaceutical organisations.

For all companies, regardless of size, acquiring a global understanding, local knowledge and deep clinical and medical expertise - whether internally or via external support - will be essential to keep pace of the changes. At the same time, clinical research organisations must demonstrate the ability to conduct safety programmes to the highest possible scientific standards - no matter where in the world they are staged - addressing critical geographical and societal variations in existing parameters for safety. It is clear that the industry's priority is to deliver on the new regulations, with a focus on global governance of safety wherever companies and research programmes are based. However, this will need to be achieved creatively, flexibly and as cost-effectively as possible to also deliver a productive and commercially viable pipeline.

The value and potential of observational studies in supporting these activities - particularly in the pre-approval phases of development - is not yet uniformly recognised. Patient registries cannot (and will not) replace randomised clinical trials,but they are one answer to regulator demands for more data on a drug's safety in the real world,with applications across all stages of the clinical trial process.

The use of systems that support drug safety monitoring, such as patient registries and anonymised patient-level databases, provides real-world data based on everyday use and valuable supplementary knowledge of drug safety while not delaying revenue generation. Indeed, earlier embracing of new approaches and solutions to the drug safety issue can offer important advantages in the longer term and potentially avoid expensive and disastrous mistakes.


Patient Registries

* Most surveyed biotechnology companies and over 50% of big pharma plan to increase their Phase IV activities over the next five years

* Companies recognise the value of patient registries post-approval; their role earlier in the development process is less well-understood

Resource Imperatives

* The need for more resources is widespread, but considered critical in regulatory departments where 50% of companies require help in the next six months

* Slightly less pressing is the perceived need for medical and commercial resources within the next 12 months


* More than 75% of respondents believed the new regulations affect the industry significantly

* Nearly 60 % felt that it is right for the industry to accept more responsibility for drug safety from early clinical trials through to post- marketing surveillance

* More than 50% indicated that SOPs are constantly updated to conformto safety regulations

*Around 75 % predicted increased work for medical and regulatory departments

* There are perceived discrepancies in the understanding of safety importance across different functions

* All companies are affected to a greater or lesser extent with a particularly notable impact on big pharma and biotech firms


Hypothesis: Companies clearly recognise the importance of the drug safety issue but there is a need for additional support at all stages of the product life cycle, to address potential resource and/or expertise requirements in meeting the changing needs of global regulators.

Research Approach: An 18-question telephone survey administered to 140 heads of pharmacovigilance, safety, and clinical research functions in pharmaceutical and biotechnology companies.

Research commissioning: ICON, a global provider of outsourced development services to the pharmaceutical, biotechology and medical devices industries commissioned IMS to carry out the research. This report is based on that research and seeks to evaluate the impact of the new regulations.

Top-tier companies were defined as those in the top 25 in terms of turnover in 2008; mid-sized companies were those ranked from 26 - 200 in 2008 in terms of turnover; biotech companies were defined as those using biotechnologies to develop drugs which may or may not yet be on the market.

Profile of Participants:

* Distribution of companies by country

* Distribution of respondents by type of company

* Distribution of respondents by area of responsibility

* Distribution of respondents by geographic scope of responsibility

Caveats: A degree of respondent bias can be assumed which explains the difference of opinion when respondents were asked to rate the preparedness of their own area or company compared to other groups or the industry as a whole.

Additionally, questions were asked about understanding the impact of the regulations on working life and future implications for the medical, regulatory and commercial functions of companies.

Only the viewpoint of the medical, regulatory and outsourcing departments were sounded in the survey, thus opinions relating to the commercial function reflect the view of these functions interviewed and not of the commercial function itself.

This article is based on the Safety First report published by IMS Health on behalf of ICON.

Readers can request a copy of the full report from Susan Dempsey on +353 1291 2057 or by emailing

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