CLINICAL DEVELOPMENT: CLINICAL TRIAL DESIGN


Dr Michael Silverman, principal at BioStrategics Consulting Ltd, discusses clinical trial design as an important aspect of the Clinical Trial Protocol.

This week I would like to discuss the importance of clinical trial design in defining a successful clinical trial protocol.

Clinical trial design provides the operational details of the drug testing conditions. It includes the specifics of trial design, use of control agents, blinding, randomization and the drug-dosing regimen. All are critical components of the scientific success of a trial, and all are closely intertwined into the superstructure of the protocol.

The study design must be created based on its appropriateness to the objectives of the trial and, in turn, is influenced by the phase of development, nature of the disease under treatment, and the availability of alternative therapy. In early, smaller trials of safety or pharmacokinetics, it may be reasonable to employ an open-label design without a control group, a crossover design, or a dose-escalation scheme. Larger efficacy trials are most commonly conducted using a controlled, blinded design, although there are many variations on this schema. The choice of design parameters must be highly individualized. There are several types of controlled trial designs, including:

Noncurrent Controls

  • Historical
  • Crossover
  • Withdrawal
  • Factorial
  • Others

Concurrent Controls

  • Nonrandomized
  • Randomized
  • Untreated control
  • Active control
  • Placebo control

The choice of the drug-dosing regimen is determined to a large extent by the products pharmacology, pharmacokinetics, and previous clinical trial results (both safety and efficacy), along with the dosage form and route of administration. This decision is often straightforward but takes on particular significance in blinded and controlled clinical trials because of the need to match dosing across study groups. It is generally possible to use a matching placebo when all groups are receiving the same dosage forms (e.g. tablets or infusions), but when the new drug has unique physical properties (such as a hemoglobin solution) or the standard therapy has a different dosage form (such as comparing an oral with an intravenous antibiotic), considerable creativity may be needed to conduct a blinded, controlled trial.

Dr Michael Silverman is the principal clinical consultant at BioStrategics Consulting Ltd., a clinical development consulting company based in Marblehead, MA, with business interests around the globe. Dr Silverman would be delighted to hear your thoughts on today’s blog, your experiences, or anecdotes and of course, your questions. To make comments or ask questions, click on this link.

FREE BIOSTRATEGIC GUIDANCE DOCUMENTS AVAILABLE:

  • CLINICAL DEVELOPMENT PLAN GUIDE
  • THE PROSPECTIVE PATIENT PACKAGE INSERT

To receive a copy of either or both, send an email to mphilip@biostrategics.com with your name and email address.

For more information: go to www.biostrategics.com or send me an email at msilverman@biostrategics.com

Copyright © 2011 BioStrategics Consulting Ltd.

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Clinical Development: The Clinical Trial Protocol Patient Population


Dr Michael Silverman, principal at BioStrategics Consulting Ltd, continues his discussion this week on the Clinical Trial Protocol. To achieve a successful protocol, the choice of the patient population is critical.

This week I would like to discuss a make or break aspect of the clinical trial protocol; the patient population.  The definition of the patient population is one of the most important conditions for testing a drug.

In many situations, it will not be the target population that is desired for ultimate labeling of the product. Early in development, or for pharmacokinetics trials, normal volunteers are often the most suitable subjects. The search for very specific or novel effects – such as unique pharmacodynamic behavior or pharmacogenomic profiles – may be conducted in small, highly selective subsets of the larger patient population. On the other hand, the potential for use in special populations may require dedicated studies in patients with, for example, renal or hepatic impairment. Eventually, pivotal efficacy trials must be conducted in a population that matches the targeted market population exactly, if the drug is to receive regulatory approval for the desired label.

From a practical standpoint, the trial population is defined by the protocol inclusion and exclusion criteria, which conceptually, fall into three distinct categories.

  • First, criteria may be used to denote characteristics that will make trial participants representative of the eventual market population – specific qualities such as age, duration and severity of disease, previous treatment and its effects, and the like.
  • Second, and particularly true of many exclusions, the criteria may have little to do with characteristics of the target population but may seek to exclude patients with concomitant conditions that may put a patient at higher risk and/or could obscure the assessment of the drug effect. Such conditions often include kidney or liver disease, malignancy, cognitive or behavioral dysfunction, or the use of certain medications.
  • Finally, several criteria are used to protect subject rights and safety, and to fulfill regulatory requirements; these include the signature of an Institutional Review Board-approved informed consent document, knowledge and ability to cooperate with the protocol, and proscription of other investigational substances within a given time period.

Next week, I will cover protocol design and sample size of the protocol. So stay tuned.

Dr Michael Silverman is the principal clinical consultant at BioStrategics Consulting Ltd., a clinical development consulting company based in Marblehead, MA, with business interests around the globe. Dr Silverman would be delighted to hear your thoughts on today’s blog, your experiences, or anecdotes and of course, your questions. To make comments or ask questions, click on this link.

FREE BIOSTRATEGIC GUIDANCE DOCUMENTS AVAILABLE:

  • CLINICAL DEVELOPMENT PLAN GUIDE
  • THE PROSPECTIVE PATIENT PACKAGE INSERT

To receive a copy of either or both, send an email to mphilip@biostrategics.com with your name and email address.

For more information: go to my web site or send me an email at msilverman@biostrategics.com

Copyright © 2011 BioStrategics Consulting Ltd.

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Clinical Development: The Clinical Trial Protocol


Dr Michael Silverman, principal at BioStrategics Consulting Ltd, initiates a discussion this week on the Clinical Trial Protocol. The protocol to test one’s product, to confirm or reject a specific hypothesis, is key in the Clinical Development Plan and in the overall development of the product with the goal of moving the science forward and preparing a product for market acceptance.

This week I would like to discuss a key aspect of the clinical trial protocol; the clinical trial objective(s). The clinical trial protocol is the experimental blueprint for a clinical study, and every activity and procedure it specifies should contribute to the efficient testing of the central hypothesis being examined.

The key Clinical Trial Protocol components include:

  • Product rationale; potential risks and benefits
  • Study objectives
  • Primary and secondary clinical end points
  • Study population; inclusion and exclusion criteria.
  • Study design
  • Investigational product
  • Study schedule
  • Procedures and Evaluations
  • Safety assessments
  • Clinical monitoring plan
  • Statistical analysis
  • Quality control and assurance
  • Ethics protection
  • Data handling and record keeping
  • Financing and insurance
  • Publication policy

If all aspects of the protocol are prepared thoughtfully and executed effectively then the clinical trial should realize its scientific goals.

Each protocol is grounded in scientific hypotheses regarding the new drug product. In fact, conducting a protocol that lacks a cogent hypothesis is not just wasteful of corporate resources, it is distinctly unethical because it exposes human subjects to an investigational substance without the expectation of generating knowledge that will potentially contribute to the ultimate benefit of patients. Thus, the statement of the protocol objectives is at the very center of protocol development.

The objectives, in turn, must be directed at gathering data that are absolutely required building blocks of the total registration dossier of the new drug. No drug can ever be completely investigated in one trial: the totality of the evidence in support of its safety, efficacy, and biological behavior is assembled from a series of trials that ask related but complementary questions.

Most protocols have more than one objective, because it is generally possible to study several closely related hypotheses in a single study. There is a limit to the number objectives that a protocol can have before the trials risk becoming so complicated that none of the objectives can be studied conclusively. Usually four or five objectives are sufficient. Similarly, it is necessary to designate no more than two or three of the objectives as primary, meaning that the scientific success of the trial is wholly dependent upon answering these questions. The other objectives, relegated to secondary status, represent questions that can also be answered under the conditions of the protocol but whose resolutions are not absolute requisites for success.

Several major categories of clinical trial objectives exist:

  • Dose-dependent objectives:
    • Safety and tolerability
    • Biological effect, pharmacodynamics, surrogate end points
    • Absolute efficacy (i.e., versus no treatment or placebo control)
    • Relative efficacy (i.e., versus an established comparative agent)
    • Pharmacokinetic behavior
    • Pharmacoeconomic outcomes
    • Effects in special populations (e.g., pediatric or renal impaired patients)
  • Non-drug-dependent objectives
    • Natural history of disease
    • Pilot data to guide the design of subsequent trials

Hopefully this gives you a sense of the importance and necessity of the Clinical Trial objective within the context of the Clinical Trial Protocol and its relation to the Clinical Development Plan. In next weeks blog, I will cover other aspects of the Clinical Trial Protocol, and if there is an area you are particularly interested in, let me know.

Dr Michael Silverman is the principal clinical consultant at BioStrategics Consulting Ltd., a clinical development consulting company based in Marblehead, MA, with business interests around the globe. Dr Silverman would be delighted to hear your thoughts on today’s blog, your experiences, or anecdotes and of course, your questions. To make comments or ask questions, click on this link.

FREE BIOSTRATEGIC GUIDANCE DOCUMENTS AVAILABLE:

  • CLINICAL DEVELOPMENT PLAN GUIDE
  • THE PROSPECTIVE PATIENT PACKAGE INSERT

To receive a copy of either or both, send an email to mphilip@biostrategics.com with your name and email address.

For more information: go to my web site or send me an email at msilverman@biostrategics.com

Copyright © 2011 BioStrategics Consulting Ltd.

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Clinical Trials: The Clinical Development Plan Part 2


Dr Michael Silverman, principal at BioStrategics Consulting Ltd, continues the discussion this week on the formulation of a Clinical Development Plan. This is a vital road map defining how one’s product will be developed through a series of clinical trials to achieve approval and market acceptance.

In last week’s blog, Dr Silverman discussed the basic framework and components of the Clinical Development Plan (CDP) and how its preparation formed one of two essential documents in support of a new compound’s strategic goals. The other essential document being the prospective patient package insert (PPI), which helps define the characteristics required of a new drug for market approval and acceptance. Formulating a prospective PPI was summarized in a previous blog. If the prospective PPI is a description of the destination, the CDP can be viewed as the map to get there. This week, Dr. Silverman further discusses the Clinical Development Plan and how to devise the map to reach your goals.

The CDP lays out a logical sequence of clinical trials that should be conducted to generate the information necessary to support the label claims. It is noteworthy to say that creating such a document, while entailing considerable time, thought and effort on the part of all members of the development team, is extremely valuable and predictive of the success of any program. Only if the perspectives of all relevant disciplines are integrated into the development plan can the project truly reflect corporate goals.

Key Components of the Clinical Development Plan (see Part 1 for the detailed list)

  • Scientific Rationale for Development
  • Commercial Rationale for Development
  • Clinical Trials Plan
  • Regulatory Considerations
  • Strategic Planning

While it is axiomatic that every program will experience unanticipated results and meet unexpected hurdles during its lifetime, an inclusive planning process creates an organization consensus about the project’s ultimate goals and criteria for success.

The CDP is a bridge between the purely strategic asset management planning process on the one hand, and, on the other, the highly tactical scientific and operational realms of the clinical trial process. Its creation is generally spearheaded by the clinical research department, which then becomes accountable for its execution.  Clinical research professionals are responsible for ensuring that every protocol contributes to the body of knowledge specified by the prospective PPI and the CDP, and that the resulting data are expressed and communicated in a way that allows corporate decision makers to act upon them accordingly.

TO OBTAIN A FREE COPY OF THE CLINICAL DEVELOPMENT PLAN GUIDE AND/OR THE PROSPECTIVE PATIENT PACKAGE INSERT, Send an email to mphilip@biostrategics.com with your name and email address.

Dr Michael Silverman is the principal clinical consultant at BioStrategics Consulting Ltd., a clinical development consulting company based in Marblehead, MA, with business interests around the globe. Dr Silverman would be delighted to hear your thoughts on today’s blog, your experiences, or anecdotes and of course, your questions. To make comments or ask questions, click on this link.

For more information: go to my web site or send me an email at msilverman@biostrategics.com

Copyright © 2011 BioStrategics Consulting Ltd.

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Clinical Trials: The Clinical Development Plan Pt 1


Dr Michael Silverman, principal at BioStrategics Consulting Ltd, talks about a second important strategic element of pharmaceutical development in this blog, and that is, the formulation of a Clinical Development Plan. This is a vital road map defining how the product will be developed through a series of clinical trials to achieve approval and market acceptance.

In last week’s blog, Dr Silverman discussed the preparation of a prospective patient package insert (PPI), a key strategic document in developing a new drug for market approval and acceptance. This week, Dr. Silverman discusses a second essential document in support of a compound’s strategic goals, namely, the Clinical Development Plan (CDP). Not to be confused with the FDA’s IND section entitled “General Investigational Plan” which is a short summary of the trials planned for the upcoming year, the CDP is an internal corporate management document.

While more tactically oriented than the prospective PPI, it is nevertheless every bit as strategic in that it serves key goal-setting, performance assessment, communications, and decision-making functions.  The CDP is again multidisciplinary and aspirational, while also providing the conceptual framework for the entire clinical trials program relating to the compound in question.

Components of the Clinical Development Plan

  • Scientific Rationale for Development
    • Chemical and physical composition
      • Chemical class
      • Chemical structure
      • Chemical properties
      • Formulation characteristics
      • Manufacturing plans
    • Nonclinical pharmacology
      • In vitro
      • In vivo
      • Secondary pharmacology
      • Absorption, distribution, metabolism, and excretion
      • Pharmacokinetic behavior
      • Pharmacokinetic/pharmacodynamic correlations
    • Nonclinical study
      • Toxicology results
      • Planned toxicology program (chronic, carcinogenicity, reproductive)
  • Commercial Rationale for Development
    • Clinical target(s) and descriptions of disease
    • Epidemiologic considerations
    • Unmet clinical need(s)
    • Unmet market need(s)
    • Market assumptions and projections
    • Product profiles: optimal versus minimal acceptable
    • Synergy with other company products (marketed or under development)
    • International considerations
    • Competitive situation (existing and potential)
  • Clinical Trials Plan
    • Phase 1
    • Phase 2
    • Phase 3
    • Postmarketing trials
  • For each phase
    • Proposed population
    • Scientific hypotheses and protocol objectives
    • Trial design considerations
    • Sample sizes
    • Projected resource needs
      • People
      • Costs
      • Clinical supplies
      • Third party vendors
    • Timelines
    • International considerations
  • Regulatory Considerations
    • Pre-IND meeting planning
    • IND documentation
    • Regulatory communications and meetings
    • Regulatory trends and intelligence
    • International regulatory planning
  • Strategic Planning
    • Milestones and critical information availability
    • Key decision points
    • Go/no-go criteria
    • Contingency plans
    • Partnering, licensing and other business development issues
    • Prospective patient package insert

For a copy of the Clinical Development Plan, please send an email request to mphilip@biostrategics.com

Part 2 of the Clinical Development Plan will be published next week, don’t miss it. Subscribe to the BioStrategics Consulting Ltd, blog (top right corner) .

Dr Michael Silverman is the principal clinical consultant at BioStrategics Consulting Ltd.,  a clinical development consulting company based in Marblehead, MA, with businessinterests around the globe. Dr Silverman would be delighted to hear your thoughts on today’s blog, your experiences, or anecdotes and of course, your questions. To make comments or ask questions, click on this link.

For more information: go to my website or send me an email at msilverman@biostrategics.com

Copyright © 2011 BioStrategics Consulting Ltd.

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Clinical Trials: Crafting the Label


Dr Michael Silverman, principal at BioStrategics Consulting Ltd, talks about an important strategic element of clinical trial design and pharmaceutical development in this blog, and that is, the crafting of the product label. This is the defining document for how the product will be used in the market place.

In the United States and other Western countries, the product label or package insert, characterizes the market for a drug by defining the indications and the appropriate patients population, informing prescribers, and serving as the basis for promotional material. Therefore, it should be self-evident that the package insert also drives development. In its most strategic context, clinical development is the process of generating the human data that populate the final package insert.

Recognizing the label’s importance, many biopharmaceutical companies have instituted formal procedures for crafting and approving, early in development, a prospective patient package insert (PPI) for every new product. This is a key planning document that articulates those developmental goals that must be realized to maximize product value. It serves as the corporate statement of those attributes a new drug must possess for it to be considered a value-adding component of the overall portfolio. Selected practical considerations and characteristics of a prospective PPI are:

The prospective PPI serves many audiences and addresses many important functions. For the development team, it provides a series of goals, raises new questions, and crystallizes thinking around central themes of development for a given product. For management, it initially serves to ensure that the development philosophy harmonizes with strategic goals; subsequently, it provides both a framework for capturing new knowledge and yardstick against which developmental progress and results can be measured. For the organization as a whole, it provides an invaluable communication and decision-making tool; at every step of the way, actual results can be compared with aspirations, and reassessment can be made regarding the wisdom of continuing investment in the project.

Central to the process of developing the prospective PPI is determining the nature of the Indications Statement as specifically as possible. No drug is ever approved with an indication to “treat infection”; instead, it is approved with a label that specifies the site(s) of infection, the causative organism(s), and the characteristics of the patient population. A crisp articulation of the Indications Statement must be made at the outset of development to provide focus and direction to the clinical effort.

Two points about the prospective PPI are worth highlighting. First, not all the new data that accrue during development and that influence decisions, emanate from clinical trials. Results are also generated by toxicology studies, manufacturing processes, competitors’ programs, and the like. Certainly, negative information about a compound’s chronic toxicity or carcinogenicity, high cost of goods, or inferior profile relative to a competitive compound will affect a company’s view of that compound’s value. Second, nota all label components lend themselves to being designed into a clinical trial but, rather, emerge from observations that are made during the course of a trial. In general, label data relating to pharmacology, efficacy, and dosing are subject to hypothesis formulation and therefore are directly designed into a protocol, whereas information relating to safety is obtained not by hypothesis testing but by careful empiric observation.

Dr Michael Silverman is the principal clinical consultant at BioStrategics Consulting Ltd.,  a clinical development consulting company based in Marblehead, MA, with business interests around the globe. Dr Silverman would be delighted to hear your thoughts on today’s blog, your experiences, or anecdotes and of course, your questions. To make comments or ask questions, click on this link.

For more information: read the rest of my blog or go to my web site,  or send me an email at msilverman@biostrategics.com

Copyright © 2011 BioStrategics Consulting Ltd.

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Clinical Trials: Three Dimensions of Success


Dr Michael Silverman, principal at BioStrategics Consulting Ltd., talks about the necessity to view the success of a clinical trial from three very different perspectives, each of which has its own unique business implications, audience and role in resource allocation decision making.

In my previous blogs, I have talked about the importance of clinical trial end points, both in terms of the choice of measure, and as it relates to the phase of clinical development. I have also talked about the commercial considerations that need to be taken into account when designing a study. In this blog, I would like to explore three very divergent dimensions of clinical trial success.  These three dimensions of success do not operate in isolation, but are closely interwoven throughout the course of drug development. They are:

  • Strategic Success
  • Scientific Success
  • Operational Success

Strategic Success

Strategic success incorporates those contributions that a given protocol makes to the organizations overall asset management strategy, as well as its role in advancing the compound’s clinical development strategy.

Asset Management: A biopharmaceutical company’s development pipeline is, in a very real sense, a collection of assets, even if they have not fully realized their potential. It is the responsibility of corporate management to maximize the value of these assets, through an asset management strategy or reasoned priority setting, targeted resource allocation, and efficient development activities. Every compound, every development program, competes for resources with every other program. The key to good priority setting and allocating resources is information: the crucial information being outcomes of data from pre clinical studies and clinical trials of products within a portfolio of drugs and studies. Which drug candidates show the most promising data, and are there enough drug candidates in each phase of study to support getting one through to approval? The audience here is clearly upper management.

Clinical Development Strategy: The clinical development process is mapped out with project milestones, decision points, go/no-go criteria, and contingency plans, and is the domain of management and its abilities to design the most appropriate work plan to obtain data necessary for regulatory approval and competitive data that will convince doctors of the drug’s safety and efficacy, patients of its therapeutic value, and payors of the overall health benefits, so as to maximize sales.

Scientific Success

In the scientific dimension, we consider the biological and pharmacological principles that provide the scientific rationale for advancing a particular compound to the clinic. Endeavors in the scientific dimension aim to establish the underling biology of the new drug and how it translates into measurable and meaningful clinical benefit. Once sufficient data is available to support moving into clinical trials, then clear clinical protocol objectives are carefully written to express the scientific questions to be asked of the new drug in a particular clinical trial. The answers to these questions are critical to understanding the drugs activity in patients, its potential clinical utility and its optimum use in the target population. They also bear directly on the product’s eventual commercial success.

Operational Success

The operational dimension deals with the real nitty-gritty of the clinical trial, where the trial is initiated and implemented, where researchers collect patient data, complete and retrieve case report forms, create databases, and analyze results. It also involves randomization, blinding, and measurement, and also powering studies, collecting sufficient patients, staying on the timeline and within the budget.  It is these areas that take considerable thought and careful planning as each one can make or break the success of the clinical trial.  However, the primary objective of operational excellence in clinical research is to ensure the integrity of the trial data. Without accurate data that reliably and unequivocally reflect the patient’s clinical condition and the effect of drug upon it, the trial results are meaningless. Success in the operational dimension means the trial is conducted in a way that neither helps nor hinders the prospects of the drug; the product is allowed to stand or fall based on its own inherent attributes. To achieve this goal is to answer the question. But sometimes data integrity is not enough; many trials fail to answer the question posed, because they were not powered correctly, or insufficient thought was given to patient randomization or drop out. So to answer the question posed, one must also ensure that data sufficiency will be achieved to allow appropriate statistical analysis to be performed to arrive at an answer one can trust.

In summary

Strategic success, therefore, encompasses both positive and negative results as long as the results lead clearly to the next step in the asset management strategy, be it proceeding, terminating or switching priorities.

Scientific success means positive results that confirm the scientific hypothesis posed.

Operational success is contingent on the accuracy and reliability of the results and having sufficient data to perform one’s analysis.

I would be delighted to hear your thoughts on these issues, your approaches, or anecdotes about decisions you have faced in similar circumstances. To make comments or ask questions, click on this link.

For more information: go to my website or send me an email at msilverman@biostrategics.com

Copyright © 2011 BioStrategics Consulting Ltd.

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