Strategy First

It would seem senseless to start the construction of a house without a blueprint, prepare an unfamiliar dinner without using a recipe or start a season aiming for a championship without a play book. Unfortunately in the biopharm industry, far too often such conventional wisdom is lost in the haste to deliver now, and the consequences can be disastrous.

(Manchan, Getty Images)

Product development challenges have never been more formidable. Recent economic downturns, along with increasing concerns regarding the safety of marketed drugs,^1,2 have captured a lot of attention. With decreasing investment resources,^3,4 mounting regulatory requirements,⁵ and stiffening competition for subject and site recruitment,^6,7 today's market will not tolerate missteps.

Gone are the days of seeding trials, exploratory fishing expeditions, do-over trials, and the like. Today, success is predicated on implementing an efficient and effective program, while calling for optimally designed trials that are conducted correctly the first time. Strategic development planning is the means to this end.

Serving a purpose

Ideally, strategic development planning should begin with early discussions prior to the start of any activity. The "guidebook" for planning is the integrated development plan. And this plan incorporates all activities related to the entire development program.

As the goal for development is to obtain marketing authorization with a desired indication statement and label claim(s), it is critical that all activities be aligned and integrated to serve that purpose. In this regard, the development plan is an excellent tool to maximize efficiency and pull together supportive information, while also serving to coordinate efforts. It ensures and reminds stakeholders that all activities funnel to a common purpose.

Despite the fact that early strategic planning requires an up-front investment of both time and money, the benefits reaped during the development program far outweigh the initial investments.

An elegant development plan demonstrates a level of thoroughness that is appreciated by regulators and investors alike. Much like an insurance policy, a development plan offers reassurance to stakeholders, providing a level of security that may be fostered over time.

The plan

The utility of a development plan lies in its ability to organize and integrate a multitude of information in one place. More than simply a list of tasks to be completed, it provides a temporal link of activities occurring across disciplines. This is of value not only with regard to streamlining activities, but also in terms of contingency planning.

The integrated development plan is essentially composed of several sub-plans, among these are:

• Clinical development plan (CDP)

• Preclinical development plan

• Chemistry manufacturing and controls (CMC) development plan

• Regulatory strategy/target product profile (TPP)

• Risk management plan (RMP)

• Commercialization plan

The preclinical, CMC, and regulatory plans are designed to support a clinical program through each study. Therefore, considerable attention must be given to their timing. For example, it is important for the preclinical and CMC plans to precede sufficiently the clinical plan to ensure there are adequate toxicology data, as well as sufficient investigational product, to support planned preclinical and clinical studies. The integration of all these activities can only be accomplished with careful risk management planning.

Marketing approval is granted based on the ability of the applicant's data to support the proposed indication and label claims. Therefore, it is imperative that each plan be crafted and constantly reevaluated against the marketing claims. Unfortunately, with personnel turnover, shifting priorities, and the occasional catastrophe, it is all too easy to get bogged down in the details and lose sight of the objective.

The Pitfalls of Poor Planning

This is where a solid development plan can mean the difference between failure and success. In summary, it is:

• A unique, comprehensive, global road map for the development of the compound

• A way to identify key decision points throughout the development, also known as go/no-go decision points

• One place where all activities, regulatory strategy, and commercial considerations are laid out

• Adaptable as new information about the product, indication, and regulatory environment becomes available

• A critical "living" reference for the development team and other stakeholders

In addition to being something that is not quickly or easily put together, the integrated development plan is also not:

A list of clinical studies. While this may be a major focus, there are other significant activities supporting the clinical program that need to be considered.

Static. Ongoing review of the plan is needed, as data from studies and other activities become available, new regulatory guidance and requirements emerge, or new information about the target indication becomes known.

Written or maintained by only one person. The complexity of the plan requires ongoing assessment and input from the entire team to fully appreciate the impact of new information.

Strategic development team

Successful strategic development planning is done by a team of experts, who should include but not be limited to the following individuals:

• Project management

• Regulatory affairs

• Clinical operations

• Medical affairs

• Pharmacology/toxicology

• Pharmacokinetics

• Epidemiology

• Biostatistics

• Pharmacovigilance

• Marketing

• Pharmaceutical development

• Manufacturing

Thinking strategically

Several core questions should be addressed at the outset of strategic planning. The answers will help define the scope and breadth needed for the integrated development plan.

Once the desired target indication statement and proposed label claims are determined, the next step is to work backward with the end in mind to shape the program based on logistical and operational considerations. The questions that should be addressed include, but may not be limited to:

• Which elements are required to support the proposed label claims (i.e., critical path) and which are nice to have?

• What resource and time constraints must be considered?

• Is this a new chemical entity or an established product being used in another indication?

• Which countries are being targeted for marketing?

• Are there any data available on this compound?

• Has any formulation work been done and, if so, is the formulation/route of administration defined?

• Are there any known safety risks with this product or other similar products?

Is there an animal model to use in toxicology studies?

• Have adequate supplies of starting materials for manufacturing an active pharmaceutical ingredient been identified? Are they of Good Manufacturing Practice (GMP) quality?

• Are there any regulatory precedents/guidances that would apply to this development program?

• What activities need to be conducted sequentially vs concurrently? What are the associated risks?

• Have any meetings or discussions taken place with relevant regulatory authorities? If so, what was the outcome?

Clinical development plan

Clinical studies and related activities provide the essential elements for the clinical development plan, including relative timelines for each study and the timing/relationship between each study. Consideration needs to be given with regard to the level of risk for a given product, and some of this risk is reflected in the relative timing of the clinical studies. Depending on the level of risk, more or less overlap can be planned between traditionally sequential clinical studies.

Strong consideration should be given to properly identifying the target patient population for each of the planned studies. If the target population is rare or presents with a life-threatening condition, additional planning may be needed to realize regulatory benefits in these situations.

The development plan will include all required studies, including examining drug-drug interactions and special populations. The plan will lay out the sample size, basic design type, timing between the studies, estimated cost for each study, and other related activities, such as regulatory. This information will be important in determining the investigational drug supplies needed for each planned study.

Preclinical initiatives

This plan should be developed after agreement on the planned clinical studies. Proper planning will ensure sufficient pharmacology/toxicology data are available to support each step of the clinical development plan.

CMC plans

Ideally, following agreement on the planned clinical studies, the chemical manufacturing and controls (CMC) development plan can be written. However, CMC work often affects the ultimate clinical plan due to formulation or other issues. This plan will provide for an acceptable stable formulation, sufficient drug supplies for each planned clinical study, stability, and preclinical studies, as well as projected manufacturing needs and plans for initial launch and marketing.

Regulatory

Use of a Target Product Profile (TPP)⁸ as an initial tool in early strategic development planning has increased in recent years. A TPP can be a significant asset in terms of helping the development team build a shared vision for the product, as well as aid in identifying data needed and the expected source(s) for that data.

In essence, the TPP is the earliest version of the EU summary of product characteristics and the U.S. package insert for the product, and it can be used to track and update the anticipated label information as development progresses. The TPP includes the regulatory strategy and other strategic considerations to drive the product forward to regulatory approval and commercialization.

The TPP also identifies significant activities and information that will be pivotal in the lifecycle management of the product under development. This TPP is a "living" document that will be updated as data and other important information become available, but it always aims to support the desired label claims.

Risk management

Recent safety concerns, observed in both pre- and postmarketing stages, have led to increased scrutiny of product safety. In this environment, a major challenge is how to expeditiously bring new products to market while ensuring public safety. As regulators continue to push for proactive safety measures, and their ability to enforce those measures expands,⁹ risk assessment and mitigation strategies will play an increasing role in product development.

Commercialization

The time from product approval to launch can vary significantly from a few days to several months.¹⁰ With millions of dollars of revenue at stake each day, it goes without saying that it pays to prepare. Careful up-front planning can pay dividends not only in terms of avoiding costly delays but also by differentiating the product from competitors and affording premium pricing and reimbursement.

Necessary steps

Strategic development planning provides a product with the greatest opportunity for success by achieving stated clinical, regulatory, and commercial objectives in a focused, efficient, and responsive manner. Beginning with the end objective in mind, the development strategy establishes critical path activities, defines go/no-go decision points, and sets general timelines and costs for the product's development.

All elements of an integrated development plan need to be worked out by a team of experts to ensure that each section addresses the product's development needs. Ongoing review and update of each part of the plan is necessary to ensure the most efficient, rapid progress toward the ultimate goal of having the product reach the market.

Whether the objective is to take the product to proof-of-concept or to obtain marketing authorization, strategic development planning is indispensable in improving the likelihood of its success.

Kenneth Lute, PhD, is senior product development specialist, strategic development solutions; Craig Eslinger, MS, MBA, is global senior executive director, strategic development solutions; and Karla Jacobus,* RN, MS, is director, strategic development solutions, for PPD, Inc., 3900 Paramount Parkway, Morrisville, NC 27560, email: karla.jacobus@rtp.ppdi.com

*To whom all correspondence should be addressed.

References

1. E. Marris, "Diabetes Drugs Under Scrutiny in a Post-Vioxx World," Nature Reviews Drug Discovery, 6, 505-507 (2007).

2. M. Kaufman, "FDA is Criticized Over Drugs' Safety Problems," The Washington Post, A05 (24 April 2006).

3. P. Mitchell, "US Credit Crunch Impacts Biotech Across the Globe," Nature Biotechnology, 26, 359-360 (2008).

4. P. Mitchell, "Investor Malaise Stalks UK, European Biotech," Nature Biotechnology, 26, 256-257 (2008).

5. R. Gliklich and M. Bertagna Leavy, "Changes in FDA's Approach to Risk," Applied Clinical Trials, 17 (10), 44-50 (2008).

6. M. Bohm, Trials and Troubles of Clinical Site Recruitment, Future Pharmaceuticals, Podcast.

7. S. Horstmann, "Global Trials Create New Obstacles," Applied Clinical Trials, 18 (1) 74 (2009).

8. Food and Drug Administration, Guidance for Industry and Review Staff Target Product Profile—A Strategic Development Process Tool (FDA, Rockville, MD, March 2007).

9. Food and Drug Administration Amendments Act (FDAAA) of 2007.

10. T. Noffke, "No Time to Delay," Pharmaceutical Executive, 7 (6) 1-2 (2007).