Step By Step
June 2007
A Q&A with industry experts highlights factors to consider when designing a clinical development plan.
The first step in any biopharmaceutical development program is to create a clinical development plan that lays out the processes, strategy and goals of the potential therapeutic. Written well in advance of the first study, a clinical development plan is a flexible document detailing the program’s key elements, such as program chronology, trial design and intended patient population. Envisage magazine asked two development experts for advice on drafting a comprehensive plan to maximize a drug candidate’s success.
Dr. Nathaniel Brown is the founder and president of Antiviral Development Consultants, in Weston, Mass., USA. Brown is a former head of clinical hepatitis research at GlaxoWellcome, in Durham, N.C., USA, and former chief medical officer of Idenix Pharmaceuticals, in Cambridge, Mass., USA.
Dr. John R. Hall is vice president and global head of the strategic drug development unit at Quintiles Transnational, in London, U.K. Hall is a former medical director at Glaxo/Allen & Hanburys, in London, and previously was associate medical director at Eli Lilly, also in London. He was a physician in clinical practice for more than 12 years and also was the founder and CEO of his own pharmaceutical medicine consulting company, John Hall Consulting Limited, for more than 10 years.
Q: “Innovation” is a current industry buzzword. What role should innovation play in the design of a clinical development plan?
BROWN | The best innovation comes from knowing the therapeutic area very well and knowing what treatment improvements are needed. When considering a clinical development plan for a new drug candidate, you need to determine what the drug can potentially contribute toward advancing the therapeutic field. Chances are good that a new drug candidate is not identical to an old drug. It usually is chemically different and has some new potential with regard to better efficacy, better safety or better convenience. To build innovation into a clinical development plan, you really need to understand what improvements are needed in this therapeutic area and how your drug can meet those needs.
You also want to look at the established efficacy endpoints and the standard safety observations for Phase II and III clinical trials in the given therapeutic area, and then determine whether innovation with regard to the efficacy or safety endpoints is appropriate in light of the current therapeutic needs. Is there a new efficacy endpoint that’s more suitable to the current medical need and which may be suitable to your drug candidate? In some cases, if a new efficacy endpoint is critical to the profile of the drug candidate, it may be appropriate to use the novel endpoint as the primary efficacy endpoint in Phase III trials. Under this circumstance, however, it is especially important to have buy-in to the novel primary efficacy endpoint by both clinical experts and the key regulatory bodies to whom marketing applications eventually will be targeted. It also is usually a good idea to include the traditional efficacy and safety measures as secondary endpoints.
HALL | Innovation can take a number of guises. There are clear U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMEA) guidelines for the development of new medicines in most therapeutic areas these days. So there’s a kind of recipe that says you will probably need this number of patients and this kind of population, and you will probably need to do two pivotal trials, et cetera. Innovation comes in the details of all of these things. For instance, should we write protocols with an adaptive design for Phase II studies? An adaptive design might enable you roll straight over from a Phase II study into Phase III, which would save the time of having to stop and analyze the data before planning a Phase III study. So statistically, there are potential innovations that one can bring in.
You also will wish to think about pharmacogenetics. You might be able to save time and money and avoid potential safety issues because you’ll be targeting your drug to a specific patient population that you can predict will show a positive response to the drug, due to their phenotype. There are many other areas like this in which innovation can save time and money.
Q: Should companies include pharmacogenetics, biomarkers and specific outcome measures in the clinical development plan?
BROWN | The clinical development team wants to obtain surrogate efficacy data as soon as possible after an Investigational New Drug (IND) application is filed, to demonstrate potential ”proof-of-concept“ for the new drug early in the clinical development program, justifying further resource expenditure. Fortunately, now there are more and more diseases that have reliable biomarkers for use in early clinical trials. There’s a lot of attention by large and small companies to make sure they’re using optimal disease biomarkers in early studies, usually targeted to surrogate efficacy assessments, but sometimes to safety assessments. Early on, you certainly want to know the pharmacokinetic and safety parameters associated with a new drug candidate, but due to the multi-million dollar costs of Phase II and III trials, it also is important to know as soon as possible if the drug is likely to offer the efficacy and safety improvements that justify its clinical development costs.
HALL | Pharmacogenetics ought to be included in the drug development plan, because the plan should be proactive with respect to what you intend to look for. Obviously not all potential biomarkers are known, and there’s always new research being published. At the very least, you should be taking blood samples from all of the test subjects, because even if you can’t predict which genetic markers are going to be affected by your compound, you want the ability to go back and analyze the data later. As events unfold and proteins and markers are identified, you can go back and re-test these samples for specific characteristics. Then you might be able to predict responders from non-responders, those who are likely to have a safety issue, and so on. There’s all manner of things you can learn if you have the foresight to take the samples.
Q: Who should be included in the collaborative effort of designing a plan? Should companies solicit the input of people from marketing, finance and clinical operations, for example?
BROWN | Once you have determined what’s needed in a given therapeutic area and the role of that therapeutic area in the company’s overall business strategy, a key goal is to get everyone’s heads together to determine the most important efficacy and safety features that must be demonstrated for the new drug. That effort must include not just the pre-clinical and early clinical development groups, but the marketing or commercial strategy group as well, because they’re the ones who are going to have to sell the drug some day.
Obviously, in small start-ups or emerging biotechs, the team around an IND is going to be smaller, but you still need to have knowledgeable people on the new drug project. Conversely, large pharmaceutical companies may have people from all the relevant functional areas already on board. Whether in a big-company or small-company setting, the clinical development leader usually should form a cross-functional project team to help guide the clinical development program going forward.
At this early stage, it is appropriate for the sponsor’s project team to determine the key desired features for the new drug’s efficacy and safety/tolerance profile, and—assuming these features are considered achievable based on the available data—the key efficacy and safety goals should be formulated into what many companies call the “target product profile” for the new drug candidate. This target product profile can guide the team in determining what trials need to be done and what the key features of those trials should be. Also, the target product profile is helpful for drafting a shell product label for the new drug, which can be a useful document for focusing the project team’s efforts going forward. As the clinical data evolve from Phase I, II and III trials, the team can revisit the target product profile and draft product label, to determine whether the new drug candidate is meeting its key efficacy and safety goals, or whether adjustments in the development program are needed.
HALL | Marketing must be involved right from the beginning. The first decision to make, of course, and one that should be kept under constant review, is whether to develop the drug any further at all, knowing what you now know. Marketing must be involved in all stages of that discussion, because you need their input on whether it is strategically beneficial from a commercial point of view to go further in the therapeutic indication, given your potential product profile. You must review a lot of market research in order to make some basic decisions. For example, you should ask physicians: If a new product came along that was able to deliver this promise for this patient population, would it be of interest, and would it be used? You need people who can make risk-adjusted net-present-value calculations, because they are the ones who can determine whether there is a financial case for developing the drug. In my view, that sort of strategic marketing is absolutely vital.
Q: What about guidance from regulatory agencies? Is it helpful to seek their advice at this phase?
BROWN | This depends on who you are as a company, and how much is known in the therapeutic area. In general, large pharmaceutical companies have extensive cross-functional expertise and usually have experience in the given therapeutic area, so they are less likely to need extensive pre-IND interactions with regulators to determine what’s needed for a new drug testing program to be considered acceptable. On the other hand, due to less staffing and often less experienced development and regulatory personnel, it often is desirable for start-up biotech or pharma companies to undertake pre-IND consultations with regulators.
Also, it’s worth keeping in mind that regulatory advice at any point can help you avoid surprises. Surprises are particularly bad for small biotech or pharma companies, whose viability in the investing world often depends on step-by-step progress with their initial drug development programs. Conversely, optimally speedy progress with individual development projects, although it always is desirable, is generally less critical for large pharma companies, which have substantial established revenues and a diverse product portfolio.
HALL | Seeking regulatory advice absolutely should be done, and it’s wise to do so at several stages. You should approach regulators right when you open your IND, or the equivalent in Europe, and then at various other stages, into Phase II and so on, until you’re confident that what you’re doing today will meet the needs of the regulators in five years’ time, as far as it is possible to predict. These days you can actually request that the EMEA and the FDA be at the same meeting in order to get joint advice when creating a global development plan. And it’s absolutely foolish not to take regulator’s advice as many times as you can.
Q: If a therapy has the potential to be developed for two indications—one to address chronic conditions, with a large potential patient population but a long development time; and another for more niche markets, which may have a quicker development time—how should companies determine which route to take first?
BROWN | The business school theory for a development program is to minimize the time to peak product sales, but that doesn’t always translate in the world of drug development. The clinical development leader almost always has limited resources, with regard to people and/or money, so the balance to consider is whether you are diverting too many resources for that small, ‘faster’ indication when you instead should be focusing on the timely achievement of data supporting the big indication.
If resources are not limited, then of course you should do both the small speedy program and the slower but larger-reward program in parallel, which would result in faster initial regulatory approval and would minimize the time to peak sales. When resources are limited, which usually is the case, in theory you should concentrate on the larger indication and not divert resources to the smaller indication, since the main goal is minimal time to peak sales. However, in my experience senior company managers often overlook the time-to-peak-sales argument, and instead often will press for the fastest time to initial product registration, as long as the initial indication is not too limited and not too far from the mainstream goals of the project.
HALL | I think you’d be looking to try to do them both in parallel if you could, depending on your company’s resources of money and people. If the one is a very small indication, then trials are going to be smaller, but they ultimately will add to the safety database of patient numbers required for the larger program. The problem comes when you have a molecule that you think, for example, might not only lower cholesterol, but also treat chronic heart failure—in other words, two potentially very important areas, each in their own right. Then you’ve got a big issue. Your cholesterol-lowering drug probably is going to be a quicker program, because the heart failure trial will be looking at survival over two or three years, so you must determine how to resource both potential blockbuster indications. An option for biotechs is to license out one of the development programs, because as an emerging biotech, you probably won’t have the resources to do both.
Q: Do you recommend planning ahead for possible post-marketing studies in the early development stage? Should companies think about the next formulation, an alternate indication or long-term safety studies?
HALL | Absolutely. The clinical development plan should include up front what else you intend to do with the drug after you’ve launched the first indication. Things certainly evolve in development programs all the time, and sometimes they can be serendipitous. By continually reviewing the data, you might determine that you can move forward with one indication now and with another one later and another one later still.
You don’t have to write 75-page protocols as an addendum to your development plan. You just need to clearly state, “If the results in Phase III are positive for this indication, then we will move on, and we will do the following in this indication.” The post-marketing objectives, as far as they can be predicted at this stage, should really be in the development plan. There’s no reason for them not to be.
BROWN | I think an increasing number of companies are making those decisions from the outset and revisiting the development plan on an ongoing basis during the initial phases. Based on consideration of the efficacy and safety features in the target profile and the needs of various patient subpopulations, the clinical development team needs to decide, early on, which of these goals must be demonstrated in critical path Phase II and III trials, and which patient subpopulations should be prioritized for those Phase II and III trials.
The team also should determine which features of the target product profile and which patient subgroups are less essential for specific inclusion in the initial product label. Such secondary project goals can be the subject of Phase IIIb and IV trials.
With regard to post-marketing studies, there is a lot of movement now among regulators toward additional large-scale collection of safety data in the post-approval period. The specific requirements and key precedents regarding post-approval safety studies are not yet evident, but this will be an area of important new considerations for teams planning lifecycle drug development programs.
Q: How flexible or rigid does a plan need to be to accommodate making decisions throughout the course of a development program?
BROWN | I don’t think a clinical development plan ever should be rigid, and the marketing plan also never should be rigid. A clinical development plan is the development team’s best guess at the pathway a drug needs to take through Phase I, II, III and into Phase IV to achieve the key goals for the project. An early clinical development plan is really just a sketch of the expected pathway, the goals of the program and the target product profile. Some flexibility is needed going forward, with constant reality checks provided by the evolving efficacy and safety data from the clinical trial program.
With regard to the schedule for updating clinical development plans, I would say they certainly need updating after each major new clinical trial is completed, with plan revisions based on what you might have learned from each key trial. Also, because the external project environment and company priorities are constantly changing, the development team should revisit the development plan on a quarterly basis at minimum, even if nothing significant is happening with regard to important new data.
HALL | The development plan must be considered a dynamic document. It should be reviewed and changed every time you get a new piece of information, such as the latest results from a toxicology study, the latest results from a carcinogenicity study or the first results from your Phase I volunteer study, and so on.
Every time you get a set of results, you should be looking at the current plan and determining whether it still is applicable and appropriate. Consider these questions, for instance: Are you still looking at the right population? Is there an emerging safety concern? Does the target product profile still look attainable? If not, should we carry on at all with this indication? All of those determinations must be made every time you get a new piece of information, and there’s no particular timeframe for that; it’s naturally just driven by data.
Q: Should companies determine the objectives for conducting pediatric studies when first creating a clinical development plan?
BROWN | The first thing to determine is whether the targeted disease is primarily a pediatric disease. If it is, then of course the clinical development program is likely to be based on obtaining data from pediatric patient populations. But if it’s an adult disease that has substantial similarities in pathogenesis in children—such as many types of common infections—the judicious approach is probably to do the adult development program first because it seems more ethical to determine a new drug’s initial safety and efficacy profile in subjects who truly can give informed consent to the risks of participating in clinical trials with unproven agents.
The other thing to keep in mind is the pending expiration of the pediatric exclusivity rule in the United States. That law, which allows an additional six months of U.S. marketing exclusivity for medicines that have been fully tested in children, has been responsible for driving many pediatric drug testing programs, and there’s serious concern now that it won’t be renewed by the U.S. Congress this year. If it’s not renewed, it could dramatically lower the number of pediatric clinical trials in the United States, since companies would have no financial justification for conducting pediatric trials for medical disorders that primarily afflict adults.
HALL | You pretty much have to plan for pediatric studies these days. There’s actually a recent directive from the EMEA that says that you must include a pediatric plan that outlines how you intend to investigate the drug in children. It’s essentially a protocol synopsis, or synopses, with information on how many studies you’re planning to conduct, and what those studies might look like. That also has to be part of the initial development planning.
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