The pharmaceutical industry provides us with proven models for the development of new medicines that are directly applicable in the small or virtual biotechnology setting. It is important that, when moving from research to development, these models are applied. Development skills cannot be acquired by staff “in process” without significant risk, and organisational and personnel changes will be required. While this can be uncomfortable, the risks, both human and financial, are too significant for not applying the right expertise and techniques as early as possible.
Research and development tends to be blended into a single ubiquitous phrase that belies the complexity of these linked but very different disciplines. All too often in small biotechnology, particularly having tried to apply research skills when in development, we don’t find out that “R” and “D” are quite different until it is too late.
Development is conducted iteratively with a heavily regulated environment and is directed to careful exploration of questions about manufacture, pharmacokinetics, efficacy and safety. It is usually performed in support of a single product, a marked differentiator from projects in research stage where a number of candidates can be explored at the same time. Further, the need for a quality process to be included in the preparation of the test product, non-clinical and clinical study procedures, data collection, assays used to measure efficacy and reporting requires a different level of organisation and new risks. Each new product emerging from the research laboratory must make a planned transition from being a research to a development project, and this must be accompanied by specific organisational and personnel changes to effectively make this transition. We can learn how best to make this transition by observing how large pharmaceutical companies, who do this routinely, organise their development, and adapt this for our smaller environment.
Of the top three pharmaceutical companies, Pfizer currently has 100 products in clinical development (31 Mar 2009, www.pfizer.com), GSK has 114 (Feb 2009, www.gsk.com), while Johnson and Johnson has 23 products in Phase III clinical trials or filed (www.jnjpharmarnd.com). The ability of companies like these to effectively churn through the development of their products is the core to preserving the value in their intellectual property. Their methods acknowledge that medicine development is a team game. They invest heavily in process review to ensure that the work is conducted optimally. The loss of revenue for each day of delay in getting a product to market when expected returns are no less than $300 million dollars per annum is clear, and this provides a strong rationale for investment in speeding up development.
In addition to the framework of procedures that each pharmaceutical company has developed, there is significant investment in selecting the right people to steer the products through development and provide those people with the necessary training. Asking a researcher to perform a development role without appropriate support and mentorship is unfair on both parties. As an inexperienced person starting in a development role in the large pharmaceutical company, you are eased gently into drug development in a process of assimilation taking many years. Training is both direct and indirect, with the majority of the learning achieved through observation of the machinations of what is, effectively, a factory for pushing products through development.
The issue for some biotechnology companies located outside of the United States and Europe is accessing that development experience. Australia has an excellent track record of contributing to the development of medicines over many years, but the reality is that the vast majority of these programs were authored and managed from overseas. Our distance from the pharmaceutical companies engaged in designing and implementing development is a limitation, and the opportunities to be a part of and learn from a development machine within our region are rare. While we remain tremendously resourceful, it is an enormous leap to undertake complex development programs without appropriate structures, support and, importantly, the right expertise at the table. In an activity with statistics at its core, not having experienced development people around the intellectual property greatly increases the risks.
The importance of having the right expertise to run and contribute to the project is starkly illustrated by drawing an analogy with the building industry, from which many of the principles of project management used in drug development were adapted. The planning required, need for team work and communication, the cost, number of people involved, time, and requirement for a multi-disciplinary approach are strikingly similar between the construction of a significant building and the development of a new medicine. Melbourne’s Eureka tower took 4 years and cost approximately US$400 million to build, Q1 on the Gold Coast cost US$307 million, and London’s “gherkin” building cost US$225 million. Given the tangible nature of a building, it is easier to see where the money is spent than in our discipline, but our out-of-pocket expenses are in a similar range, leaving aside the opportunity costs of failed products along the way. And we are similarly dependent on bringing technical skills to bear while marrying regulatory, financial and scientific risk.
Building programs start with significant investment in design and planning, including who is going to perform which steps, when those steps will be performed, and what the interdependencies are. Everything down to the finish of the rooms is planned, documented and agreed, and getting the best contribution from each of the people engaged to work on the project is an integral part of the plan. At the risk of stretching the analogy, while you may never intend to take the construction right through to occupancy, the potential partner you hope to attract is going to inspect your plans, your regulatory compliance, the commercial opportunity and very closely inspect the foundations you lay. In other words, you will need to demonstrate that you know what you are doing. So it is with drug development. Given the similarity in scale, and commercial and human impact, the rationale for approaching the development process with a similar degree of rigor should be apparent.
Careful planning and active management are fundamental to success in any development program, and the preparation of the Development Plan (DP), including the Target Product Profile (TPP), should be the starting point for each development program long before the work begins. Often the best place to start the planning process is to write the indication statement as part of the TPP, and the best place to start this is by reviewing the existing indication statements and Prescribing Information (PI) for similar products or products in the same therapeutic area. This will provide guidance about which populations were studied, what endpoints were used, and what other supporting data were provided to achieve licensure. The indication statement is the distillation of all data and, effectively, the license about who can and who cannot be treated. All data generated will serve to support the indication, which makes it an ideal place to start the planning process.
The DP structure is a matter of personal preference, but, in general, it should be broken into the constituent subprograms that should include chemistry, manufacture and controls (CMC), toxicology, research, regulatory, clinical, pharmacoeconomics, and commercial, with each functional expert providing their input. DPs should include details of all of the steps involved in the development of the product, with a high level of detail over the first one to two years, the milestones/decision points, the rationale for the approach taken, responsibilities and the budget for the work. One way to view the role of the DP is as a form of contract between the company and the development team, allowing the latter to say what steps they will take, why that path was chosen, and how much it will cost. The former have a clear understanding of the objectives and are able to monitor progress without having to make decisions on minutiae as the program progresses. It is incumbent on the development team to report back on progress and seek approval for material changes to the workplan (such as delays, or the requirement for additional studies) while having the freedom to operate within the constraints of the approved workplan. It is also helpful to have the rationale for decisions made as there is a natural human tendency to go back over old ground, and to capture corporate knowledge should key people move on.
There is risk at each stage of development and the DP is the place where those risks are prospectively identified and strategies for mitigation are planned for and documented. Unlike the building industry, the medicine development process will change as new data emerge. The systems need to be in place to deal with that inevitability. Part of the mitigation of risk is to discuss and agree a position on a particular issue that emerges at the project team level, to validate those decisions with external advisors, and to discuss the company’s position with the appropriate regulatory authorities.
While it is acknowledged that the DP and TPP continuously evolve during the life of the program, they remain critical documents to ensure that the development team are clear on their objectives and provide a blueprint of the development program for new staff, boards, and potential investors.
Organisation of Development Teams: The Project Team
The development of medicines requires a diverse group of people who each contribute their functional expertise as well as their general scientific and logistical skills to the achievement of the common development objective. The development process depends on effective collaboration between people with different domain expertise who may be located in different departments, companies and/or countries. It requires thorough coordination of effort of all participants to ensure that the right skills are brought to the benefit of the project at the right time. The project team structure is employed throughout the pharmaceutical and biotechnology industry to achieve these goals and should be established early in the development process (once a candidate has been selected for clinical development) and remain with the project throughout its life cycle.
The project team is responsible for preparing the workplan in the DP, and then delivering that work in accordance with the agreed finances and timelines. The team coordinates the specific-functional activities necessary to develop each candidate through subprograms, which are led by experts in the respective fields. Functional area-specific decisions and issues should be resolved at the subprogram level, leaving issues with a cross-functional impact to be discussed and resolved at the project team. To keep the project team meetings manageable, it is not uncommon to have only one representative from each functional area as a project team member, although how the project team is managed is a matter of personal preference.
In the smaller biotechnology company, the same person may fulfil the leadership of more than one subprogram, and frequently contractors will be used to lead a particular function. However, with few exceptions, this should not change the operation of the project team. The roles and responsibilities should still be clearly defined and the work expected of each person described in the DP. It is often the human factors and, in particular, communication, that can be the downfall of a complex project, and paying attention to this can mitigate the risk of failure. Utilising the project team structure helps greatly to provide clarity of roles and responsibilities for the team as a whole as well as for the individual members. Further, the accountability for actions and decisions made through peer review brings an emphasis on transparent decision making that is based on the data. Arguably, most people perform better when there is peer accountability and there is important benefit of balancing the performance of individuals, those stronger and weaker, in a collective.
A project team also has an often under-emphasised role in ensuring that projects that should be consigned to history are considered more objectively. It is natural to become attached to projects the longer they exist, but this can cloud the judgement about the suitability of continuation. Having broad membership of the project team helps to bring different perspectives to the thorny question of when the horse really is dead.
With few exceptions, the project team must be led and their activities supported. This is generally achieved through the appointment of a project leader, and this person is supported by a project manager.
Management of Development Programs
The leadership of the project team is the most critical hire for the development program. It is clear that the person to whom you entrust the company’s most important and complex activity should be adequately experienced (preferably with both operational and therapeutic area expertise, although the combination is rare) with the right personal attributes. A global search for this person should be considered.
Specifically, the project leader sets the priorities and directs the activities of the project team, using the DP as the workplan. They are the conduit for issues from the project team to senior management and vice versa. In the large pharmaceutical company setting, the project leader is often drawn from the project team based on their experience and leadership qualities, but it should be noted that project leadership should change over time to reflect the stage of development (for example, a project in pre-clinical toxicology might be lead by a toxicologist).
While having a project leader is relatively uncontentious, the support of a project manager for the project leader may seem like a harder investment to justify, particularly at the early stages of development. However, in reality, it is the project manager who is the day to day pivot point for the project team. Although the role includes the very practical activities of coordinating meetings, gathering agenda items and writing minutes, this is anything but an administrative role. The project manager is scientifically trained and works with each subprogram to provide a project-wide perspective. They will ensure that potential issues at the subprogram level are identified and brought to the attention of the project team. The project manager also ensures that budgets, activities, timelines, and milestones across all functions are tracked and reconciled with the DP. The project manager achieves this through the use of project planning software, which they frequently update. The resultant Gantt chart is able to help the project leader and project team identify the critical path and critical activities, resource constraints, and the impact of slippage in one area on the whole program.
The project leader and project manager set the tone of communication for the project team. It is important that they utilise open, transparent communication based on good scientific principles, that they are inclusive and foster the contribution of all project team members and other experts as required. Clear leadership is important, but a domineering style is rarely effective at fostering the best from the project team.
Outsourcing your clinical trial
The contract research organisation (CRO) providing clinical research services can be a superb partner in the implementation of the development program. Not all are the same and there are optimal ways of working with your selected partner so that both parties get the maximum out of the experience. One of the criteria for success is understanding from the outset what your respective strengths and weaknesses are, and playing to them. It should be viewed that, when a CRO is engaged, a large number of people are added to the development team, and the selection should be made with this in mind.
CROs are excellent implementers of clinical trials and, with appropriate reassurance from a tertiary (independent) source, will ensure that your work is compliant with the regulations. However, the company developing the product is the Sponsor (a role that is defined in the International Committee on Harmonisation Good Clinical Practice) and the Sponsor continues to carry the obligations associated with that role despite outsourcing some or all of the activities. The company is also best placed to steer the science behind the protocol, so while elements of protocol preparation, data collection tools, endpoint definitions, data analysis and reporting can be outsourced, it is optimal to invest in these specific issues within the company with support from the CRO. Note that even with a fully outsourced clinical trial, there will need to be internal resource to manage the CRO. It is a fallacy that, because the protocol is outsourced, it needs no internal management.
Like all parts of the development process, a critical factor is the people committed to your project and their experience and capabilities. Being able to judge who is being engaged and what they bring to the development program will be a critical time and money saving skill. In the global head offices of CROs are a number of highly experienced development scientists who have been through registration processes who can add significant value to the program. It is a matter of knowing that you need different skills for different elements of the development program.
Each new product emerging from the research laboratory must make a transition from being a research project to a development project, and this must be accompanied by specific organisational and personnel changes that are challenging. The risks of not doing so are numerous: failing to generate appropriate data, using the wrong endpoints, trying to squeeze too many variables into studies, not including enough subjects, including too many subjects, not achieving the required regulatory standards, skipping crucial steps, not properly defining safety, using the wrong dose range, of wasting money by failing to plan, changing direction mid-stream, collecting the wrong data, collecting too much data: the list goes on. Development expertise is indispensable and the search for the right person should be global.
There are few absolutes in medicine development, which is why it is important to reach a consensus on the grey areas with a team. There are no doubt some phenomenally talented people who have the ability to pull a development program together and get it right first time. For the rest of us, enhancing the chances of success by following the proven pharmaceutical industry model of planning carefully, finding the right leadership and team members, and documenting the process prospectively and retrospectively will take the guess work out of your one shot at success.
Medicines Development Limited (www.medicinesdevelopment.com) is a not-for-profit organisation with the objective of developing new medicines and vaccines for the developing world.