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REGULATORY : Comprehensive Guide for Generic Drug Trials  The Unique Concerns of Recombinant DNA Research  TRIAL DESIGN : A Crash Course in Adaptive  Also in this issue : Sponsors Challenged by Globalization, GCP Inspections Unite EMEA and FDA, Post Credit Crunch R&D Opportunities

Applied Clinical Trials Digital Edition - September 2009

Clinical research in India has again come under scrutiny. A comprehensive new market report has highlighted the pros and cons of organizing trials in India, and in the wake of a case of suspected fraud, the regulators have issued new guidelines for CROs. 

 Number of Phase III Trials Started in 2008			

India is a very attractive cost-value proposition, but tax incentives are lacking and infrastructure weaknesses continue to be a problem, according to the authors of "Taking Wings: Coming of Age of the Indian Pharmaceutical Outsourcing Industry," published by Ernst & Young and the Organisation of Pharmaceutical Producers of India. 

Strong growth has occurred in recent years, particularly in Phase II and III clinical trials (see chart). The fiscal constraints on global pharmaceutical and biotech companies have contributed to this growth, along with the Indian government's commitment to support the life sciences sector. The Indian population's strong technical drug chemistry skills, as well as the responsiveness of sites, have also helped. Data protection and exclusivity are still major areas of concern, however. 

"There are no provisions in Indian laws regarding whether the data collected from clinical trials can be used by the Drug Controller General of India in its approval procedures for other drugs," the authors note. "In addition, there is a debate about whether data exclusivity laws need to be enacted in India." 

You can download the report free-of-charge at 

Meanwhile, the New Delhi-based regulatory authority, the Central Drugs Standard Control Organization (CDSCO), has issued draft guidelines that require the registration of CROs that conduct human studies on drugs, cosmetics, and medical devices. Under the guidelines, CROs must adhere to SOPs to obtain a license of registration, which is valid for five years. CDSCO is currently seeking feedback on the proposed changes. 

"This is an attempt by the government to control scientific and ethical standards for clinical trials in India," said Nermeen Varawalla, MD, MBA, president and chief executive officer of ECCRO (Emerging Country Contract Research Organisation). "It reflects the government's keenness to promote the sector and the realization that highest standards are critical for the sector to thrive. Hence, they are a good thing and a significant statement to the international community, although in themselves, the impact of these rules will be less significant." 

Also in India, suspected fraud has prompted Glenmark Pharmaceuticals to close its clinical trial site at Guru Gobind Hospital, Jamnagar, Gujarat. At the site, Omnicare Clinical Research was conducting a Phase IIb study for Glenmark's chronic obstructive pulmonary disease/asthma product, Oglemilast. 

During monitoring activities immediately after initiation of the site in late 2008, Omnicare suspected fraudulent activity, and the clinical investigator, A. Bhattacharya, MD, has now been suspended.—

Global News

Indian CROs face new guidelines as the country's clinical trial market continues to face infrastructure issues.

The Spotlight Falls on India

TCN 5.0 expands metrics and risk mitigation for key areas

announces TrialCentralNet (TCN) 5.0, its patient recruitment management system for sites and sponsors. TCN 5.0 features a robust communications infrastructure, tools for proactive planning of enrollment efforts, targeted site selection criteria, a recruitment development and implementation process, efficiencies for patient enrollment, and instant reporting on randomization and retention metrics. 

In addition, TCN 5.0 features improved graphical interfaces for study site personnel and improved function across multiple browser platforms. The new version can be integrated with other clinical data systems as well as other TCN eSystems related to patient recruitment. 

Protocol Manager 8.0 Delivers Web Availability

CRAs' needs also addressed in upgraded version of software

 announced its Protocol Manager Version 8.0 CTMS, which now features Web-enabled access to authorized users worldwide. Also, a new Clinical Study Portal designed for CRAs joins the already existing portal for investigators. 

Winchester CTMS developers have retained the IBM Lotus Domino platform, citing its broad offerings for workflow and application security. In addition, it eliminates the need to obtain separate components to serve as database manager, collaboration manager, email router, security system or Web server. 

Winchester customers can purchase or upgrade to Version 8.0 CTMS by Enterprise Adoption, a traditional licensing model, or choose the optional hosting pricing model, featuring Software as a Service and paying on a trial-by-trial basis. 

Winchester Business Systems, (781) 203-0200, 

Clinical Quality Management Solution addresses process and compliance 

 announced TrackWise Clinical Quality Management Solution to provide end-to-end streamlining of clinical trial processes and ensure compliance with global regulatory standards. This extension of the TrackWise enterprise quality management system (EQMS) begins with preclinical activities through manufacturing and postmarket operations. 

TrackWise Clinical Trial Quality Management Solution provides closed-loop process support to allow issues to be reconciled and corrected before they escalate. The solution manages incidents, structured audit programs specifically tailored around clinical trial execution, the associated CAPA and change control processes, as well as trial registration and trial documentation/SOPs. 

eShowcase

The latest eclinical software in the clinical trials industry.

eClinical Software: September 2009

The recent wave of merger and acquisition activity among pharmaceutical and biotechnology companies is strong and likely to continue through 2010. Some of the most notable transactions during 2008 and 2009 to date include Pfizer's acquisition of Wyeth; Merck's agreement to purchase Schering-Plough; Takeda Pharmaceutical's acquisition of Millenium Pharmaceuticals; Eli Lilly's unexpected bid and acquisition of ImClone Systems; and Roche's hostile bid for Genentech. 

The rationale for M&A transactions seems straightforward enough: Large and mid-size companies typically pursue mergers and acquisitions to build up their pipelines and to strengthen their market positions. Small sponsors have traditionally pursued being acquired in order to secure more capital for R&D investment or as an exit strategy. But in practice, mergers and acquisitions appear to either fall short of expectations or to impact drug development spending and productivity in unintended ways. Speak with anyone who has lived through a merger or acquisition and you'll receive an earful of experiences and anecdotes supporting this statement. 

Earlier this year, my Tufts Center colleagues and I conducted a study to quantify the impact of M&A transactions on drug development spending and productivity. We analyzed transactions announced and completed between 1998 and 2004. Our findings shed some light on what happens to drug pipelines and R&D spending post-transaction and offer insight for sponsors, CROs, investigative sites, and financial professionals into forecasting and anticipating the impact of M&As. 

Tufts CSDD analyzed development pipeline and spending data from published sources on 24 of the total 26 major independent transactions among 41 merged and/or acquired companies completed between 1998 and 2004. Major deals were defined as those that exceeded $1 billion in transaction value among publicly-traded independent entities. Two transactions were not included in the analysis because one was acquired by a larger company during our observation period and the other lacked sufficient data to allow for our detailed analysis. Also, organizations that are subsidiaries of diversified holding companies were not included in our analysis. 

In order to understand sponsors' development pipelines and spending practices prior to an M&A transaction, my colleagues and I looked at published development data for each of the companies involved nearly two years before the transaction announcement. We then compared that retrospective data with pipeline and spending data two years and four years after each transaction was announced. 

Transactions were also organized into subgroups: "Large" versus "Small" acquirers, for which the former group had to include one of the 20 largest pharmaceutical companies by revenue at the time of the merger; and "Mergers" versus "Acquisitions," the latter being defined as transactions implemented by buyers whose annual revenue is more than three times larger than that of the acquired party. 

Companies that go through a merger or acquisition consolidated their portfolios, particularly transactions involving smaller companies. Pipeline consolidation was likely due to a number of factors. Following a transaction and during the integration period, companies tend to trim their portfolios to free-up and reallocate resources. Projects deemed noncore and marginal are the first to be cut along with those that lack an internal champion or have not been adequately resourced. 

The typical biopharmaceutical company saw a 6.4% annual increase between 1998 and 2004. But companies that went through a merger or acquisition saw a significant 2.9% annual decrease in the number of drugs in their development portfolios from two years prior to four years after the transaction announcement. This decline was most pronounced among merged and acquired companies in Phase III, where the number of drugs dropped nearly 7% each year. For the industry benchmark the number of drugs in Phase III studies saw relatively flat annual growth (0.5%) between 1998 and 2004. 

Annual growth rates in the number of drugs in Phase I studies were similar for merged or acquired companies and the industry benchmark. The annual growth rate in the number of drugs in Phase II for merged and acquired companies was considerably slower (3%) compared to the industry benchmark (8.5%). 

Small acquirers saw substantially higher contraction (10.1%) in the number of drugs overall in development two years prior to four years after the transaction. This compares with a 1.6% decline in the number of drugs in development overall for large acquirers during that period. Both small and large acquirers consolidated the number of late-stage Phase III drugs in development. In Phase I the annual growth rate in the number of drugs for both small and large acquirers increased more modestly relative to the industry benchmark. Large acquirers saw substantially higher annual growth rates in the number of drugs in Phase II than did small acquirers. 

Merged entities consolidated the number of drugs in the pipeline overall and in early Phase I studies. Acquisitions on the other hand saw substantially higher annual growth in Phase I activity compared with merged companies and the industry benchmark. The number of drugs in Phase II development for companies that merged grew at annual rates well above industry benchmarks. Both merged companies and acquisitions consolidated their Phase III programs. 

Annual growth in R&D spending is substantially higher for companies that have gone through an M&A—particularly smaller acquisitions—compared to that of the industry benchmark. Following the completion of a transaction, the combined organization must confront integration challenges, resource uncertainty, and operational instability. 

During integration, drug developers tend to reallocate a higher proportion of their financial resources outside of R&D. As a result, they must rationalize their portfolios in order to adequately invest in priority projects. Companies may also be allocating more resources and time to leverage the value and synergies of the combined entity after the transaction is completed. 

Merged and acquired companies increased their overall R&D spending significantly by 14% annually beginning two years before and ending four years after the transaction announcement. Small acquisitions increased R&D spending 19.2% annually—10 percentage points higher than the average annual R&D spending growth rate among large acquisitions. The typical company increased R&D spending annually by 10.8% between 1998 and 2004. Among merged and acquired companies, annual R&D spending growth rose the fastest (23%) during the period two years to four years after the transaction announcement. 

Compared to industry benchmarks, merged and acquired companies have higher Phase I and Phase III failure rates and higher success rates in Phase II. Merged and acquired companies have trimmed their late stage portfolios and therefore development risk is spread across fewer candidates. Higher attrition rates may also be due to integration uncertainty, particularly personnel turnover associated with M&A transactions and other resource allocation issues. 

Among companies completing a merger or acquisition, 46.4% of compounds in Phase I failed compared with the benchmark failure rate of 30.8%; 46.6% of the compounds that made it to Phase II were terminated compared with the benchmark rate of 58.8%; and 29.9% were terminated in Phase III compared with the benchmark rate of 21.5%. 

Having completed a merger or acquisition, sponsor companies face substantial integration challenges and uncertainty leading them to consolidate their pipelines while increasing R&D spending at a faster rate each year than industry norms. For service providers—including CROs, investigative sites, central labs, eCT solutions providers—M&A transactions present unprecedented, and increasing, volatility. 

Under the current economic environment, large and mid-sized pharmaceutical and biotechnology companies are bullish about finding acquisition bargains. Company valuations are low and many smaller organizations are desperately seeking capital. In turn, larger, better-capitalized organizations see a buyer's market for enriching their pipelines and their R&D talent pool and capabilities. Our recent study begins to quantify the impact of M&A transactions on portfolio and R&D spending growth.

 MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: 

Clinical Trial Insights

Mergers and acquisitions volume is way up, but have they fulfilled their intended purpose?

Into the Aftermath of M&A

By the time you read this, transatlantic cooperation on Good Clinical Practice will have passed a new milestone. As from September 1, 2009, the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) will have launched their joint initiative to collaborate on international Good Clinical Practice (GCP) inspection activities. The two sides will share information on inspection planning, policy and outcomes, and on the conduct of collaborative inspections. 

The justification for this innovation is that it will help protect clinical trial subjects in the face of increasingly globalized clinical research. As the EMEA says, in defense of the scheme, "in most cases" the same clinical trials are used to support marketing authorization applications in the European Union and new drug applications and biologics license applications in the United States. 

The scheme has become possible because of confidentiality arrangements that have been established recently between the EU and the FDA. It will look at GCP-related information contained in applications for scientific advice, orphan medicines designation, pediatric investigational plans, and marketing authorization or postauthorization activities of significant public health interest. 

Thomas Lönngren, the EMEA's executive director, speaks warmly of "the increasing collaboration" between his agency and the FDA. He sees this latest move as "an important step to the building of a global regulatory network for supervision of clinical trials." 

In any case, limited inspection resources mean that "only a sample of sites and clinical studies can be inspected." So on a more empirical and local level, the cooperation should certainly save some time and energy, or, as Lönngren puts it: "By working together in a collaborative and synergistic manner, GCP inspection resources can be used more efficiently." Notably, the exchanges should make the selection of studies and sites "well informed." 

The initiative has been started with an 18-month pilot phase, which will focus only on products regulated by the Center for Drug Evaluation and Research in the United States and by the EMEA for the centralized procedure. But over time what is envisaged is the periodic exchange of GCP-related information, collaborative inspections, and systematic mutual alerts on GCP-related legislation, regulatory guidance, and related documents. 

The results expected by the authorities will be streamlined inspection planning, faster and more effective communication of inspection outcomes, alignment of inspection procedures, and, over time, a closer sharing of interpretation of GCP, allowing the two sides to "act together to benefit the clinical research process." The cooperation is, says the EMEA, designed to build mutual understanding of, and confidence in, the GCP inspection processes. Trial sponsors can help too, says the EMEA, by informing regulators in the United States and EU of a joint filing, which can be coordinated in both regions. 

Anyone conducting a clinical trial who is curious to know more about how this is going to work can get real close to the action. The EMEA and FDA are inviting volunteers to participate in a collaborative inspection during the pilot phase. The opportunity is there to sign up "to engage in dialogue and planning of joint inspections involving applications that are anticipated to be submitted fairly simultaneously to both agencies within the next 12 months." 

				Getting improved information flows is also identified as a priority in the just released 2009 compendium of health data from the Organisation for Economic Cooperation and Development (OECD).

"The demand for health-related data is high," it remarks—adding that "one of the main obstacles limiting meaningful analysis of health care systems has always been, and still is, the lack of sufficient coverage and availability of health care statistics." As if to prove its point, the OECD offers a striking paucity of information on the pharmaceutical aspects of health care across its 40-plus member states. While noting a generalized increase in pharmaceutical spending to 17.1% on average in 2007, the latest year for which it provides data, its own summary provides figures on only a handful of the 27 EU countries. 

In the Czech Republic, where pharmaceuticals accounted for 21.5% of total health spending, the increase is, says OECD, "one of the factors behind the rise in total health spending." A "strong rise" in pharmaceutical spending, to 31.2%, has had a similar effect in Hungary, which holds the dubious distinction of ranking first among OECD countries for spending on pharmaceuticals as a proportion of total health expenditure. 

Pharmaceuticals accounted for 24.5% of total health spending in Poland, ranking it fourth among European countries for this proportion of spending on pharmaceuticals—coming also behind the Slovak Republic's 27.9% and Greece. In Portugal, the figure was 21.8% and in Spain 21%. 

"The need for internationally comparable data is on the rise as national administrations seek to evaluate their health care systems against those of other countries," OECD remarks—with justice, given the increasing trend toward health technology assessment as a mechanism for limiting the access of new medicines to the market. But OECD admits that at present its statistical tool is still "in the process of development," and "its accuracy and the consistency of series...are to be refined." 

There are few generalizations about pharmaceutical spending in Europe that can be drawn from the OECD data as they stand. One tentative inference—confirming the findings of other analyses—is that the north/south split in the EU not only persists, but that the high proportional spending on pharmaceuticals in the "Club Med" countries of southern Europe is largely mirrored in the EU's new member states from central and eastern Europe. Meanwhile, the more puritanical north is keeping spending on pharmaceuticals as a percentage of total health expenditure. 

In Germany, pharmaceuticals accounted for 15.1%, while in Austria and Sweden the figure was only just above 13%, and in Denmark just 8.6%. Even here, however, the share of total health spending allocated to pharmaceuticals has nonetheless increased over the past decade. 

The EU has decided it is time to update its current recommendations for the clinical development of lipid-lowering and blood pressure-lowering agents. At present, the EU accepts the possibility of drug registration for so-called biological indications, permitting demonstrations of efficacy through their effect on biological markers (LDL-cholesterol and blood pressure respectively). Now it wants to bring more clarity to this policy, to explicitly state where these principles would not be applicable, and where further data on the effect of these medicinal products on morbidity and mortality would be required before a marketing authorization is issued. 

As a note from the EMEA remarked at the end of July, use of surrogate markers as proof of efficacy for drug approval has been a matter of debate. While use and validation of biomarkers in drug development is encouraged—they "may play a critical role in the early prediction of the effect of a drug in terms of both safety and efficacy," says EMEA—for drug approvals, complete information for a sound benefit-risk assessment may not be provided by the proof of efficacy of a surrogate. 

So it is no longer content merely to ensure that product information highlights the limitation of the data on which an authorization has been granted, and that no suspicion on a detrimental effect on morbidity and mortality is found. These recommendations should be further detailed, it says, in order to allow applicants to anticipate in which situations outcome studies might be required before a marketing authorization is issued. 

				The plan is to revise guidance by specifying the type and level of detail of the clinical and nonclinical information expected for a proper evaluation of the safety profile of a new medicine, in relation to key organs and systems (notably cardiovascular, renal, and hepatic safety). Discussion will also cover how far the quantity and quality of information should reflect the mechanism of action of the medicine (such as whether there is known class toxicity, or if it is a new class of drugs).

What should emerge from all of this, by early next year, is a safety evaluation algorithm that will help establish the need for outcome studies and whether they will be required pre- or postauthorization. It should "provide guidance to industry when performing trials to develop lipid-lowering and antihypertensive drugs, and also provide a clear basis for the EU authorities when assessing data and providing advice on these types of drugs."

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium. 

View from Brussels

The globalization of clinical research leads both sides of the Atlantic to collaborate on GCP inspections.

EMEA and FDA Team Up on GCP

 When it comes to partnerships there are an array of factors that will effect the relationship—one of them being a company's size. With size as an influence, the question burns, do sponsors seek out similar sized providers? 

When we asked our audience this question at 

, 65% voted yes, only 6% no, and the remaining 30% had never heard of this trend. Now the question turns to, why? 

One possibility, according to Denise Calaprice-Whitty, PhD, executive director of The Avoca Group (Princeton, NJ), is that smaller sized sponsors "appear to be substantially less efficient in their management of providers. Top ten companies have more structured strategies and systems for managing providers." 

A recent survey conducted by this company asked respondents, "Has your company been successful in forming truly strategic relationships with CROs?" This generated a response of 61% yes from top ten companies and only 31% yes from small, midsized ones. 

While first instinct may lead to the belief that larger sponsors receive more attention from providers because they have larger pipelines with greater budgets—and though this may be a realistic assumption—large sponsors will simply always have more resources and manpower to better manage partnerships. 

Large sponsors "appear to have more focused outsourcing strategies, more outsourcing tools and templates, and better means of measuring CRO performance and relationships and for sharing this information," Whitty elaborated. 

The survey also asked respondents if their companies had a formal set of relationship metrics to evaluate its relationships with clinical service providers and 48% of top ten companies said yes versus 12% of small or midsized companies. 

"We have seen that smaller sponsors are more likely to be dissatisfied, as opposed to having neutral feelings" about work performed for them by providers, Whitty noted. 

Though evidence of this trend may not be concrete, recent alliances have followed suit: Eli Lilly–ICON, ProTrials–Medivation, and Pfizer–Almac. 

In following Whitty's explanation, sponsors must choose a provider based on management capabilities. So, a small or medium sized sponsor should not select a CRO that is larger than itself. Doing so would put the sponsor in a position of biting off more than it can chew and potentially contribute to an unsatisfactory relationship.—

News

An exploration of how a company's size influences partnerships.

Does Size Matter in Partnerships

To ensure commonality of understanding, establishing what is meant by "adaptive trial" is warranted. A working definition of an adaptive trial is as follows: An adaptive trial is one that uses information obtained within the study to modify, or potentially modify, the structure or other design feature of the study. 

 (JOSE LUIS PELAEZ, JON BOYES, GETTY IMAGES   ILLUSTRATION: PAUL A. BELCI) 

From the perspective of statistical analysis, an adaptive design can affect alpha (require some adjustment for multiplicity) or can preserve alpha without adjustment for multiplicity, where alpha is the probability of a type I error—which most commonly is the probability of declaring that a drug is effective when it is not effective. In early phase development studies where alpha has no important role, adjustment to alpha is not essential because it is not relevant. 

It is noted that when a study includes a provision to make a modification (e.g., an interim analysis with a reassessment of the sample size), the study is considered to be an adaptive trial whether or not a change was made. Also, when a study does not include a provision to make a modification but a modification is made through the amendment process, the study is considered to be an adaptive trial (e.g., if it is determined that the sample size will not support the study's achievement of its goals and a decision is made to modify the sample size). When information within the study is used to make a modification or potentially to make a modification, then the study is an adaptive study. 

By contrast, in a traditional clinical trial a protocol is developed and executed with no modifications—ideally. Amendments are tolerated, but when there are too many a stigma is attached to the study. Introducing flexibility in a clinical study is contrary to the well-planned, well-executed nature of the traditional study. 

One driver of the traditional plan-your-work and work-your-plan approach to research is to protect alpha—the probability of a type I error, which, in the context of a placebo controlled superiority study is the probability of concluding that a drug works when it doesn't. The rigid nature of the traditional trial protects the statistical analysis from inflated alpha for efficacy evaluation. 

Another driver of the traditional approach to planning the study and executing it without modification is the protection of the study against sources of bias. Knowledge of results of the study can influence the accruing results, thereby damaging the study's integrity. A traditional study often mitigates this kind of bias by using an independent Data Monitoring Committee for reviews of unblinded data or accumulating results. 

This source of bias is an issue for an adaptive study because the protocol includes provisions to alter the study structure or other design feature. The risk of this bias should be evaluated in the context of the overall goal of the study and its role in the drug development plan; if this bias is not important in context, then the risk is low. If the study is intended to be used as a source of pivotal evidence of efficacy, this bias would be important. 

Although adaptive trials are not new, there is a new enthusiasm for the flexible methodology, and the recent popularity is in part related to encouragement from the regulatory arena for creative pathways to shorten timelines to bring new therapies to market. Regulatory agencies have communicated that, under certain conditions, flexibility in a trial can be acceptable.

EMEA issued a document, "Reflection Paper on Methodological Issues in Confirmatory Clinical Trials Planned with an Adaptive Design,"

  (See Table 1) and FDA has as a published PDUFA goal the release of a draft guidance shortly. It should be emphasized that encouragement from regulatory agencies to make use of adaptive trials is accompanied by caution against inappropriate use. 

Table 1. Synopsis of the EMEA views on adaptive design based on a document issued in 2007.  

Regulatory risk depends on the regulatory role of the study. If the study is not used as a basis of approval, regulatory risk is minimal. There must be adequate basis for dose selection, but demonstrating statistically significant differences between the selected dose and a de-selected dose is not required. 

If the alpha associated with the analysis of differences between doses is inflated, it is of little or no concern to regulatory agencies if the evaluation of efficacy does not rely on that study for key support. Confirmatory studies need to be uncompromised. For basis of approval, the issue still goes to weight of evidence. If remarkable efficacy is found, some compromise can be tolerated. If the study conclusion is less robust, compromise becomes more of an issue. 

The regulatory risks are truly scientific risks as well. There are, however, other scientific risks that would not be of particular concern to regulatory authorities. If the study does not have an important regulatory role, then the regulatory agency would not be concerned with the compromise, hence the sponsor bears the scientific risk. 

In an adaptive study, presumably in early development, when data review occurs as data is accrued, it is tempting for sponsors to make decisions based on small amounts of data. While having a small amount of data is better than having no data, there is still risk of over-interpreting the trends (favorable or unfavorable) and making wrong decisions. Including statistical assessment as a routine part of the clinical and medical evaluation can help to mitigate this scientific risk. 

When a later stage study is planned as adaptive, scientific compromises are introduced when the personnel involved in the ongoing study receive information about accumulating results about the study. 

In any study with compromise, whether traditional or adaptive, the evidence of efficacy must be sufficiently substantial to overcome obstacles of potential bias or inflated alpha. 

Benefits of an adaptive design are clear: potentially shorter timelines, fewer subjects exposed to de-selected doses or treatments, fewer subjects in a study, and less cost. The adaptive design permits a study to adjust to the accumulating body of knowledge and data pool to guide continued clinical research. [The most common types of adaptive studies include modifications of the type listed in Table 2.]  

Table 2. A description of the types of adaptive design modifications and adjustments to alpha needed. 

An adaptive trial that includes more than one study under the same protocol permits a small (or pilot) study to be done followed immediately by another study without the delays and resource investment of study start-up. Pilot studies are useful in situations where data are not available or are too limited to support the required decision making. 

It should be noted that an adaptive design is not a remedy for poor planning. In the absence of good data to plan a study, an adaptive study can include doing a pilot study within the larger study. A scenario could be that an initial dose is selected for evaluation, data are collected, analyzed, evaluated, and the next step in the program is made on the basis of real data as opposed to relying solely on animal data and guesswork. 

In the context of an adaptive study, the pilot study is just the first segment of the study, and the following segment, which is actually a new study, is administratively conducted within the same protocol—same IRB, same sites, same visit schedule, same administrative staff—and enormous efficiencies are gained. 

An appropriate risk assessment for the evaluation of the appropriateness of permitting flexibility in a study requires the context of the role of the study and the role of alpha. In a Phase I study, alpha is not generally very important. 

If resources only afford three treatment arms in a study, and the appropriate dose is known to be one of five arms, an adaptive design can offer a solution. Risk is increased if the wrong doses are evaluated in a study. 

Generally, in early phase drug development adaptive studies carry little risk. The regulatory risk is low in early phase development because these studies are not used as a basis of pivotal evidence of efficacy. Scientific risk can be mitigated by adhering to sound scientific principles. 

In late phase drug development, adaptive studies can be extremely beneficial or risky. Phase II/III studies can avoid "enrollment holidays." The scientific principles, which are also discussed by regulatory agencies, must be protected; compromises to scientific principles carry risk. In late-phase studies, regulatory acceptability is a key consideration. Communication with the appropriate regulatory agencies is strongly advised to ensure acceptability of the study by the agencies. 

Appropriate and complete risk assessment includes balancing the potential benefits of an adaptive study against the risks associated with the adaptive nature of the study. All studies have some risk, however, and the risks of doing the traditional study must also be considered when making the decision for the study being planned to be traditional or adaptive. 

If the assumptions and available data underlying the design of the traditional study are tenuous, then those risks may be greater for the program than those associated with the study being adaptive. In planning the study, inserting safeguards to protect the integrity of portions of the study that may be suitable for registration can allow the sponsor to have the benefits of an adaptive study while simultaneously protecting the integrity of the study intended to provide pivotal evidence of efficacy. 

These safeguards relate to shaping the protocol to include an operational adaptive plan that includes a pivotal study within the adaptive study. The pivotal portion would have a separate randomization, and the statistical analysis plan would treat the data from the pivotal portion of the study as if it is a stand-alone study. 

Another risk that warrants a notation in the planning of an adaptive study relates to the operational infrastructure. When a decision is made to do an adaptive study, the operational aspects of execution of the adaptive study need to be able to support the decision. The standard operating procedures (SOPs), templates for key study documents, and personnel training need to include the flexibility. Additional documents, or additional major sections in existing documents, may be necessary to ensure seamless operations. 

For example, when a study arm is discontinued, reclaiming the clinical trial material intended for use by that study arm needs a process. If the organization makes a decision to execute an adaptive study but does not have the operational details addressed, there can be risk to the study. 

In early phase development, adaptive trials offer beneficial flexibility with little or no regulatory risk. In confirmatory trials that are used as a basis of pivotal evidence of efficacy, modifications of an ongoing study can compromise the study integrity and should be used with caution. In an adaptive study that includes pivotal evidence of efficacy, there should be randomization that begins the pivotal portion of the study, and there should be no modification or compromise to the study after the first subject has been randomized into that part of the study, and that part of the study should be able to stand alone. 

, PhD, is the vice president of data sciences strategic services, clinical research services, and 

,* MD, MS, MPhil, MBA, is corporate vice president of data sciences, clinical research services, at PAREXEL International, email: 

*To whom all correspondence should be addressed. 

1. S. Gottlieb, Speech at Conference on Adaptive Trial Design, Washington, DC, 

http://www.fda.gov/NewsEvents/Speeches/ucm051901.htm

 2. Hung et al., "Adaptive Statistical Inference Following Sample Size Modification Based on Interim Review of Effect Size," presented at ASA Joint Meetings (2002).

3. J. Woodcock, "FDA's Critical Path Initiative —Progress to Date and Direction," presented at the Science Board to the FDA, Gaithersburg Hilton, Washington, DC, December 3, 2007. 

4. EMEA, "Reflection Paper on Methodological Issues in Confirmatory Clinical Trials Planned with an Adaptive Design," at 

http://www.emea.europa.eu/pdfs/human/ewp/245902enadopted.pdf

Feature Article

Understanding and using adaptive trial design to achieve the most of its available advantages.

An Assessment of Adaptive

• Currently a member of BARQA and the Institute of Clinical Research, 

 will now serve as the head of quality assurance at 

 (Glasgow, UK) Glasgow-based headquarters, where she will manage the global quality assurance team and further develop and deliver a quality strategy for the company. 

• Being recognized for her services to the pharmaceutical industry for the past 20 years, 

, PhD, the senior vice president and head of worldwide pharmaceutical sciences for 

 (New York, NY) has been made an Officer of the Order of the British Empire in the Queen's Birthday Honors celebrations. 

 will bring with her quality assurance background in both pharmaceutical manufacturing and R&D to her new position as head of quality assurance for 

• The Vice President of Clinical Data Management and Regulatory Operations for 

 (Newtown, PA) eClinical Service Division, 

, has been elected as the Drug Information Association North American Special Interest Area Communities eClinical Chair. 

• Bringing with him more than 25 years of experience in the areas of scientific computing, biostatistics, bioinformatics, programming, and global data management, 

 (Princeton, NJ) data management and biostatistics for Phase IIIb/IV clinical trials, patient registries, and observational studies as he serves as the new vice president of global data management and biostatistics for peri-approval services. 

• Previously the senior director in clinical research operations specializing in patient recruitment at 

, PhD, is now serving as the vice president of 

 (Boston) Start-up and Accelerated Recruitment Team (START). 

• Being an accomplished senior executive and having developed several life sciences companies throughout his career, 

, MD, will now serve as the new chief executive officer and director of 

 (Rockville, MD) as the new Senior Strategist and Vice President of General Medicine, 

 will utilize over 10 years of provider and sponsor experience designing and directing patient recruitment programs. 

• Now leading the customer delivery group as the Chief Operating Officer, 

 will be responsible for global operations within the services branch of 

• Upon the opening of a new office in Brussels, 

 as the new country manager for Belgium and The Netherlands. 

• As the new Senior Vice President of Neuropsychiatry to 

 (Raleigh, NC) Central Nervous System team, Tom Zoda, PhD, will be responsible for providing senior level oversight of all psychiatry and neurology projects on a global basis.  

Six academic medical centers and research institutions—the 

University of Texas M.D. Anderson Cancer Center, Columbia University

Duke University, University of Kansas, University of Miami

—will form an advisory group that will collaborate with 

 (Fremont, CA) to develop a Service-Oriented Architecture for the company's eResearch CTMS deployed at each of the institutions.

Department of Clinical Chemistry of the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital

 (Amsterdam, The Netherlands) will begin development of a potential therapy for brain tumors.

Following an agreement from November 2008, 

 (Indianapolis, IN) has signed another strategic partnership with 

 (Dublin, Ireland), which will have the company manage Lilly's clinical trial set up and monitoring in Europe.

To launch and manage the ImproveCareNow Collaborative, which allows selected practice sites to work together to improve the care of Crohn's disease and ulcerative colitis, 

 (Morrisville, NC) and Improve Care Now have extended a partnership.

 (Rennes, France) as a certified partner, making it one of only a few partners around the world that are recognized by Mortara for adhering to the HL7 annotated ECG standard used by the FDA to manage its data warehouse.

With many top pharmaceutical companies having a presence in Saudi Arabia and in order for the region to attract more commercial attention, group delegates from some of the leading institutions and pharmaceutical companies based in the country participated in the 

 (Bourne End, UK) clinical trials and clinical trials practice course.

Working closely together for over a year, 

 (Watertown, MA) have entered into an alliance to reduce the failure rate of drugs in late development, particularly due to toxicology.

To develop a purpose built translational medicine facility, 

 (Dublin, Ireland) has entered into a collaborative agreement with the 

Central Manchester University Hospitals Foundation

, a full-service CRO specializing in clinical monitoring and data management services, has been launched by 

 (Zurich, Switzerland) in response to a growing demand by European and U.S. pharma companies for clinical trial support services in India from already established providers.

In an effort to enhance discovery and development of affordable and effective therapies for visceral leishmaniasis (kala azar), the Drug Discovery Unit of the 

 (Geneva, Switzerland) have decided to collaborate.

 (Research Triangle Park, NC) has won the 2008 Pfizer Development Operations' Strategic Supplier Excellence Award for demonstrating consistent and excellent performance in the areas of quality, service delivery and reliability, innovation and business processes, and customer service and responsiveness. 

 (Research Triangle Park, NC) to its "100 Best Places to Work in IT," for its second year in a row, moving from 37th to 16th place.

Frost & Sullivan's 2009 Clinical Trials Management Product Innovation of the Year Award has been awarded to 

 (San Ramon, CA), recognizing the company's EDC and CTMS platform, Prism.

The Institute of Clinical Research's Education Manager Sue Fitzpatrick shaking the hand of Abdullah Aljoudi, MD, after he completes one of the organization's clinical trial courses recently made available in Saudi Arabia. 

 (Austin, TX) product line is the Biosafety Solution, which automates the medical research study protocol process, from protocol inception to approval, as is required by the Institutional Biosafety Committee.

Association of Clinical Research Organizations

 (Washington, DC) has lent its support to the "Patient-Centered Outcomes Research Act," which was introduced by 

 also supports a related House bill introduced by 

 (Woburn, MA) now provides instant access to its Protocol Manager Version 8.0.

 (King of Prussia, PA) has achieved Rave Accredited status, enabling the company to build Rave EDC databases independently and provide other Rave EDC programming related tasks for clients.

 (Greenville, NC) surpasses what it refers to as a significant industry milestone, which is its 100th first-in-man Phase I study.

With the launch of a new, redesigned Web site, 

 (Chapel Hill, NC) has changed the look of its site, but the Web address remains the same, 

' (King of Prussia, PA) Regulatory Document Management System will be built to support and validate documentation for the DIA Electronic Document Management Reference model.

Industry news focusing on the people and organizations who work in the clinical trials profession

Applied Clinical Trials-09-01-2009

Applied Clinical Trials Digital Edition - September 2009

The Spotlight Falls on India

eClinical Software: September 2009

Into the Aftermath of M&A

EMEA and FDA Team Up on GCP

Does Size Matter in Partnerships

An Assessment of Adaptive

Business and People Update September 2009

eCTD Training Efforts

Global Development Challenges Sponsors

Regulating the Generic Drug Process

Post Credit Crunch Opportunities