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Complexities of oncology

Innovation in this field is an essential, and potentially well-rewarded, activity, but costs and risks need to be controlled and collaboration is the key
Pasta orange

Given the fact that statistics show cancer rates rising unremittingly, there is a renewed emphasis on cancer research and development. More than 1,000 oncology compounds are currently in development and a significant share of the overall industry R&D spend is dedicated to oncology. Historically, the rewards have been big. Blockbuster drugs Avastin, Rituxan, Herceptin and at least seven others each generate more than $1bn in annual global sales.

Development risks
However, the development risks and costs are substantial and growing. It is clear that the more that is understood about the scientific basis of cancer, the more complex it becomes. Two patients with a similar diagnosis and the same treatment may show very different responses and outcomes. A cancer diagnosis, be it lung, breast, colorectal or another, requires an understanding of how that specific disease originates and how it progresses and spreads in the human body.

The trend towards targeted therapies and companion diagnostic tests means that identifying representative clinical trial patients will be even more challenging than it is now, as only a fraction will meet the traditional inclusion/exclusion criteria. That factor will increase development costs, slow time-to-market, and potentially lead to a limited label.

Acceptable oncology clinical trial endpoints appear to be moving targets, often influenced by the varying positions taken by regulatory authorities, medical academics and patient advocacy organisations. This uncertainty adds a considerable amount of risk and instils a defensive (and costly) posture by the innovator company. Tumour response, progression-free survival and overall survival are among the intermediate and final endpoints that must be measured, but often they are given different weightings by different authorities.

Unique environment
The recent US Food and Drug Administration (FDA) interest in, and emergence of, combination therapies during clinical trials, similar to the 'cocktails' used to treat HIV, also leads to more complex trials, requiring multiple companies to work together in a unique situation. At the same time, a more active, educated and engaged cancer patient population expects more manageable side effects from the cancer treatments of the future.

In turn, the European Medicines Agency (EMA) is facing the key challenges of how to proceed with the authorisation of biosimilar drugs. Because these products are derived from cell culture or whole living organisms, there is bound to be a degree of variability in any attempt to copy them. However with many patents on biotech drugs ready to expire, it is essential that some licensing mechanism for such drugs is established.

To complicate matters even further, financial pressures related to private and public payers are challenging reimbursement levels for cancer drugs and treatments. Companies must evaluate the payer perspective and how they define the value of oncology drugs.

Looking at the US and Europe, for example, there are any number of influencing variables, from reimbursement systems, patient numbers to currency fluctuations, Health Technology Assessment (HTA) mechanisms, pricing, medical culture and patient access schemes that drive the market.

These variables also occur between and within European markets, with their relative sovereignty in health policy, different pricing and reimbursement approaches, as well as the further influence of regional or local budget management.

Countries such as France and Germany are seeing a growing mandate for more aggressive HTA. Due to budgetary constrictions, the EU has to ensure that expensive new therapies are chosen and used in the most efficient way possible. For example, HTA can look into whether a new drug is more effective in the treatment of a specific cancer than other alternatives already in use.

One indication of this environment, and the rapid overcrowding in more traditional oncology categories such as non-small cell lung cancer and breast cancer, is a rising interest in orphan indications for cancer drugs.

The pipeline of candidate drugs for cancer is full, but many of these will not make it through phase III clinical trials and cost-based rationing is bound to prevent patients from accessing many of those that are registered.

For example, this is shown in the UK, where drugs that are readily available in continental Europe are often rejected by the National Institute for Health and Clinical Excellence (NICE) on cost-effectiveness grounds.

The industry is facing a genuine dilemma as costs skyrocket and reimbursement challenges multiply. Are clinical development programmes designed to deliver incremental improvement in cancer care a thing of the past?

Sea change
If they are to achieve continued progress towards a cure for cancer, pharmaceutical and biotechnology companies need to address a central issue: how should oncology clinical development be transformed to manage the risks and costs better?

The pipeline of candidate drugs for cancer is full, but many will not make it through phase III clinical trials and cost-based rationing is bound to prevent patients accessing many that are registered

Matched treatments
The use of biomarkers to match the most effective treatment with each individual patient will remain the focus in the industry. This remains true despite the reality that having a smaller initial patient population makes it harder to recover development costs. The investment in biomarkers will be justified by the higher price that a more effective drug commands and by additional product lifecycle opportunities that will boost the revenue potential.

Early decisions on strategy
Given the significant risks and associated costs of oncology clinical development, key product strategy and go/no-go decisions need to be made early in development. Doing so requires a deep understanding of a compound's mechanism of action and of future standards of cancer care.

In particular, critical product positioning decisions (such as whether the treatment is first- or second-line, stand-alone or combination) must be made early, and must be based on scientific and commercial insights. Access, reimbursement and other payer issues are key factors in these decisions.

When there are major uncertainties, parallel development of agents within organ-defined patient populations (for example, colon, breast, lung, prostate) may be required to maximise the scope of eligibility for individual patients. More precise targeting of specific agents for individual patients may help minimise clinical trial costs and greatly accelerate the development timeline for these agents.

Redefined endpoints
To accelerate speed to market, companies need intermediate endpoints that accurately reflect global clinical benefit and are acceptable to the regulatory agencies. Developing such early metrics is challenging, in part because of the complexities and variability of the patient care pathways. Further complexity results from the fact that multiple interventions may occur during a given patient's care, as each intervention used may confound the 'gold standard' endpoint of survival. Identification of new, valid short-term endpoints that are widely accepted across the industry by investigators, payers and regulators remains a vital, but as yet unmet, need.

Understanding competitors' pipelines and critical areas of clinical need are important in developing a clear and certain direction and timeline for product approval. Successful trials will change the standard of care and set a higher bar for efficacy and tolerability.

Speed to market
Once a strategy is set, patient enrolment, trials execution, data analysis and dossier preparation must be managed as a process to be continually optimised. Early involvement of the regulators and, in some situations, payers, will make it possible to prepare for rapid decisions and to determine acceptable data points for approval and reimbursement.

Collaboration
The upcoming wave of product innovation in oncology and the advent of personalised medicine hold an exciting promise: a world with improved cancer care that far exceeds the tedious, incremental progress that has characterised cancer developments until now.

However, rapid improvement of outcomes will require collaboration between stakeholders, including pharmaceutical companies, patient groups, regulators, investigators and payers. This collaboration is the only way to maintain a reasonable balance between accelerating safe access to innovative care and managing the cost of care to a level tolerated by society.

Life science companies need to seize opportunities in the oncology therapeutic area by forming alliances with partners who will enable direct and immediate access to academic, government and community practice research. They should look to gain from creative, oncology-specific approaches to solving complex challenges in research, development and commercialisation and search out guidance and direction about oncology drug discovery, early and late stage clinical development and all aspects of the commercialisation of oncology products.

Together with these partners, they will gain practical, specific recommendations and implementation support to help them succeed in the evolving and complex market that is global oncology.

The Authors
Carmen Allegra is managing director, Novo Oncology Associates and Keith Morris is principal, Capgemini

To comment on this article, email pme@pmlive.com

10th August 2011

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