The cost and time to bring new drugs to market are staggering, and it is not getting any easier, quicker or cheaper, which means longer waits and more expensive treatments for the most part.

The latest figures presented at a recent industry conference in 2011 suggest that the time to bring a new drug through the preclinical, clinical and regulatory approval process is approximately 13-15 years and costs approximately $1.2 billion. If the cost of failure is added in, it is closer to $2 billion.

The statistics are staggering. In 2007, Morgan Stanley estimated that to end up with one drug in the market, it is necessary to screen 5-10,000 molecules which are then whittled away through testing for safety and efficacy towards are particular treatment of a disease, which means you have to be ready to invest in 9,999 other molecules that will fail. Thomas Edison springs to mind. Certainly most molecules are abandoned before testing in man, and only the best, most active and most likely not to cause harm move into the clinical phase of drug development. As a product enters clinical trials the probability that it will eventually gain approval for marketing is quite low. In 2011, the latest probabilities of success relating to the start of a clinical phase in a drug’s development, were reported as follows:

Stage of Development               Probability of Approval

• Phase 1                                                       9%
• Phase 2                                                     15%
• Phase 3                                                    44%
• Submission                                            80%

The “Success Rates” at different phases of clinical testing was also reported.

Clinical Trial Phase      Probability of Success

• Phase 1                                    63%
• Phase 2                                    33%
• Phase 3                                    55%
• Approval                                 80%

It is not totally surprising to see that most of the failure occurs in Phase 2 clinical studies. Phase 1 clinical studies are largely focused on safety in man, and have already been broadly tested in a number of animal models before hand. However, at Phase 2 the clinical studies are not only larger so one can discover more regarding toxicities, but it is at this stage that the ability of the drug is usually first tested to see if it is effective in bringing about the required therapeutic effect. This is where many drugs stumble.

In the larger still Phase 3 or pivotal clinical studies it is here where the drug is exposed to a broader array of patients and has to show strong statistical evidence that the drug is effective and safe. Although overall the success rate is 55%, the rate does differ between different therapeutic areas:

Probability of Success at Phase III by therapeutic area:

Therapeutic Area                                 Probability of Success

• Autoimmune:                                             63%
• Respiratory:                                               61%
• Endocrinology:                                          60%
• Infectious disease:                                     55%
• Neurology:                                                  55%
• Cardiovascular:                                         46%
• Oncology:                                                   34%

The lowest success rate is in the treatment of cancer where we still have a long way to go to truly understand all the mechanisms in play.

Drug development is not for the feint of heart. It is highly risky, expensive, and takes a long time to realize a return, if any. The strategy and tactics behind testing these products in man clearly must be done with considerable planning and thoughtfulness by an experienced team of drug development professionals.

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:

1. The Clinical Development Plan Guide
2. The Prospective Patient Package Insert Guide
3. The Clinical Trial Protocol Guide

To receive a copy of the guide(s), visit Contact Us page or send an email to mphilip@biostrategics.com with your name and email address.

For more information: go to the BioStrategics Consulting Ltd website or send me an email at msilverman@biostrategics.com

BioStrategics Consulting Ltd provides a range of management-level clinical development consulting services to the pharmaceutical, biotechnology and medical device industries, including: Clinical development strategy and management, conceptualization, implementation, and management of Phase 1, Phase 2, first-in-man, and proof-of principle clinical trials, IND planning and preparation, FDA and other regulatory authority submissions, meetings, and related interactions, Clinical strategic planning for small molecules, biotechnology products, immunotherapeutic agents, novel drug delivery technologies, and medical devices in virtually all therapeutic areas, New technology assessment, due diligence, and program planning, Clinical development advisory services to senior-level management (CEO, COO, CSO, BOD).

Copyright © 2011 BioStrategics Consulting Ltd.

The study is complete. All patients have been enrolled, treated and followed for the required amount of time, all data has been collected and recorded, all Clinical Report Forms (CRFs) have been filled out and audited, the database has been locked, and the statistical analysis is finished. Did the trial succeed?

Defining the success of a clinical trial can be a subtle and complex undertaking, wholly dependent upon the criteria used to determine success and the use to which the information is to be put.

In a large Pharma or Biotech company, it is likely there is a portfolio of areas in which the company is working, and in each area of product development, there are probably several compounds in development as part of the strategy for different disease areas or product types. A hypothetical company is illustrated in the table below, which represents a large biotech company with an extensive portfolio, and representative compounds are used as examples.

Clinical Trial Success Levels & Responsibility

1. Asset Management Strategy Success – Policy & Portfolio Decisions

2. Clinical Strategy Success – Clinical Strategies for Each Compound

3. Scientific Success – Protocol Design to answer Scientific Questions

4. Operational Success – Protocol execution, data collection, management and analysis

In this model, policy, along with the portfolio that the company will pursue, is set at the level of asset management strategy and flows down to the other levels. At the level of clinical strategy, management decides how each compound should be developed to achieve the goals set by the policy makers. The next tier is responsible for ensuring the clinical trial protocols are designed to address specific scientific questions and the managers below this level then ensure operational success by overseeing the running of the study, data collection, auditing and analysis. Essentially, clinical trial results are communicated upward in the model from the operational level to the asset management level. At each level the results take on a different context and drives different decisions. In each context, clinical trial results are evaluated for their conformance to success criteria relevant to that dimension. Thus, a trial that meets one audience’s criteria for success may fail dismally in another context.

For example, in an oncology program, a given trial may be operationally successful: there is a high degree of confidence that the data represent the true clinical effects of the drug, and that the data integrity has been maintained throughout the process. However, this confidence does not ensure scientific success. If the protocol called for an inappropriate patient population or insensitive assessment techniques, the protocol still may not meet its stated objective, it may show, for example, that the drug was not able to reduce the volume of the tumor targets. If the clinical trial is operationally inadequate, there is no hope of meeting its scientific objectives because the data will be deficient.

If the trial succeeds scientifically, there is still no guarantee of success on the clinical development dimension. If a hypothetical oncology trial met its stated objective of not having an effect on a specific tumor, the product would probably not advance to the next phase of the clinical strategy. On the other hand, if a clinically important effect were shown, clinical development success would be a given. Finally, a trial that fails to meet its scientific objectives is a failure from all perspectives. If the trial provides no conclusive results, it provides no useful information toward determining clinical development or asset management strategy.

By extension, it can easily be imagined that a trial that advances the clinical development strategy also benefits the asset management strategy. At the same time, the asset management dimension occupies a unique position in that it may succeed even if one, two, or all three of the subsidiary dimensions record a failure. For example, as part of asset management strategy, it may be stated that an oncology compound must enter Phase III trials by a given date or lose its place in the portfolio to another, more promising, oncology product. Such a strategic intent can be realized even if the product fails at other levels. If the deadline is not met, the plan will proceed with a different product, satisfying asset management goals. Lastly, if a trial succeeds at the operational, scientific and clinical development strategy dimensions, it will certainly succeed as a component of asset management strategy.

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:

1. 1.     The Clinical Development Plan Guide
2. 2.     The Prospective Patient Package Insert Guide
3. 3.     The Clinical Trial Protocol Guide

To receive a copy of the guide(s), visit Contact Us page or send an email to mphilip@biostrategics.com with your name and email address.

For more information: go to the BioStrategics Consulting Ltd WebSite or send me an email at msilverman@biostrategics.com.

BioStrategics Consulting Ltd provides a range of management-level clinical development consulting services to the pharmaceutical, biotechnology and medical device industries, including: Clinical development strategy and management, conceptualization, implementation, and management of Phase 1, Phase 2, first-in-man, and proof-of principle clinical trials, IND planning and preparation, FDA and other regulatory authority submissions, meetings, and related interactions, Clinical strategic planning for small molecules, biotechnology products, immunotherapeutic agents, novel drug delivery technologies, and medical devices in virtually all therapeutic areas, New technology assessment, due diligence, and program planning, Clinical development advisory services to senior-level management (CEO, COO, CSO, BOD).

Copyright © 2011 BioStrategics Consulting Ltd.

I previously discussed clinical trial operational success from the viewpoint of Getting the Right Data, which involves site selection, clinical assessments, laboratory procedures, clinical supplies and biological specimens. Last week I discussed Getting the Data Right, which encompassed Case Report Form (CRF) design and clinical monitoring. This week I will discuss data management, statistical programming and analysis, and quality assurance.

Data Management

Data management transforms raw Case Report Form (CRF) data into the electronic version that can be ordered, organized, reorganized, transferred, analyzed and archived. Data professionals are responsible for ongoing quality checks, query generation and resolution. It is their job to ensure the integrity of the clinical data as it undergoes its transformation from CRFs to complete data sets that can be then subjected to extensive statistical analysis.

Statistical Programming and Analysis

The biostatistician oversees the processes that group, summarize, analyze, and otherwise present trial data for clinical interpretation. These processes often include statistical computer programming as well as development of the analysis plan, conduct of primary and exploratory analyses, and preparation of data tables, listings, and figures for display and communication.  The project statisticians, in conjunction with the clinical team, produce the final study report, an interpretive document whose validity rests, once again, on maintaining the integrity of the clinical data at every step in the process.

Quality Assurance

Quality assurance activities permeate the clinical data pathway. Whether conducted by professionals within each department, or by an independent department (or even contractors), quality assurance checks and extensive audits further increase confidence that each datum in the final database can be traced with accuracy to its counterpart at the clinical site. In critical situations – most commonly, Phase 3 trials generating pivotal efficacy data for registration purposes – the audit process is extended externally to include key clinical investigative sites as well.

These final phases of the clinical trial process are critical to ensure one is ready to interpret the data. The source of the data has to be confirmed, properly recorded and assigned to appropriate fields within the database, before the statistical program is run. After several further checks, the final step prior to interpretation of the data is the so called  “data lock”, when the data set is finalized and locked so it can no longer be changed, corrected, or moved to different places. It is this “locked data” which is then interpreted.

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:

1. THE CLINICAL TRIAL PROTOCOL GUIDE
2. CLINICAL DEVELOPMENT PLAN GUIDE
3. THE PROSPECTIVE PATIENT PACKAGE INSERT

To receive a copy of the guide(s), visit Contact Us page or send an email to mphilip@biostrategics.com with your name and email address.

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

BioStrategics Consulting Ltd provides a range of management-level clinical development consulting services to the pharmaceutical, biotechnology and medical device industries, including: Clinical development strategy and management, conceptualization, implementation, and management of Phase 1, Phase 2, first-in-man, and proof-of principle clinical trials, IND planning and preparation, FDA and other regulatory authority submissions, meetings, and related interactions, Clinical strategic planning for small molecules, biotechnology products, immunotherapeutic agents, novel drug delivery technologies, and medical devices in virtually all therapeutic areas, New technology assessment, due diligence, and program planning, Clinical development advisory services to senior-level management (CEO, COO, CSO, BOD).

Copyright © 2011 BioStrategics Consulting Ltd.

Over the last two weeks I discussed clinical trial operational success from the viewpoint of Getting the Right Data, which involves site selection, clinical assessments, laboratory procedures, clinical supplies and biological specimens. Over the next two weeks, I would like to change directions to discuss Getting the Data Right, which encompasses Case Report Form (CRF) design, clinical monitoring, data entry and management, statistical programming and analysis and quality assurance.  This week will concentrate on Case Report Form Design and Clinical Monitoring.

Case Report Form Design

The case report form (CRF) is the data capture tool of record for any industry-sponsored clinical trial. The CRF must be thoughtfully created to gather all relevant trial information as it becomes the basis for the evolving electronic database.  As such, many team members must participate in its development; clinicians with their understanding of the nature and flow of clinical procedures; data managers, with their perspective on the creation of a useful, high quality database; and biostatisticians, with a view toward meaningful data presentations and analyses.

Lack of attention to CRF design can be a critical lapse with far reaching downstream reverberations. In a study I was involved with sometime back investigating a treatment for cervical dysplasia, the CRF contained a field to capture post treatment cervical histology, but restricted the entries to abnormal results only and would not allow for tissue that was normal to be recorded. Several patients actually finished the study with normal histology, yet there was no CRF field for recording such data. As a result, the final database never listed the normal results, generating endless confusion and almost leading observers to erroneously conclude that the desired result of “normal” had never been observed.

Clinical Monitoring

Clinical monitors (or clinical research associates [CRAs]) are the linchpins of efforts to ensure data integrity. They are the only professionals in the position to compare the sponsor’s records (i.e., the CRF) to source documentation; to constantly monitor adherence to regulatory and ethical principles; and, in countless other ways, to ensure compliance of study procedures with Good Clinical Practices. At all steps of the data retrieval process, the highest value is placed on accuracy, honesty, and attention to detail. The clinical monitor carries that message to the world outside of the investigative site.

A well thought through Case Report Form and well trained and experienced clinical monitors are critical to ensuring you get the data right and go on to completing a successful clinical study.

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:

1. THE CLINICAL TRIAL PROTOCOL GUIDE
2. CLINICAL DEVELOPMENT PLAN GUIDE
3. THE PROSPECTIVE PATIENT PACKAGE INSERT

To receive a copy of the guide(s), visit Contact Us page or send an email to mphilip@biostrategics.com with your name and email address.

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

BioStrategics Consulting Ltd provides a range of management-level clinical development consulting services to the pharmaceutical, biotechnology and medical device industries, including: Clinical development strategy and management, conceptualization, implementation, and management of Phase 1, Phase 2, first-in-man, and proof-of principle clinical trials, IND planning and preparation, FDA and other regulatory authority submissions, meetings, and related interactions, Clinical strategic planning for small molecules, biotechnology products, immunotherapeutic agents, novel drug delivery technologies, and medical devices in virtually all therapeutic areas, New technology assessment, due diligence, and program planning, Clinical development advisory services to senior-level management (CEO, COO, CSO, BOD).

Copyright © 2011 BioStrategics Consulting Ltd.

Last week I discussed operational success from the viewpoint of Getting the Right Data and specifically choosing the right clinical sites. This week I would like to discuss Getting the Right Data from the standpoint of standardized clinical assessments, centralized laboratory procedures, managing clinical supplies, and managing biological specimens.

Standardizing Clinical Assessments

It is absolutely imperative that those clinical assessments that are critical to study outcome be measured the same way at every site, for every patient, at every time point. This requirement means that outcomes measures should be made objective to the extent possible; that all investigators will be trained to use standardized diagnostic techniques; and that, when relevant, the same diagnostic equipment be used at each site.

For example, in a clinical trial of glaucoma therapy, the primary end point of drug therapy is intraocular pressure. A variety of techniques exist for measuring pressure, and even the same technique may encompass several different machines having different calibrations, performance criteria, and normal ranges. Failing to standardize procedures across sites creates enough noise to obscure any signal coming from the drug. Standardization can be achieved relatively easily by providing the same model tonometer and the same training to all investigators.

Centralized Laboratory Procedures

Similar considerations apply to laboratory testing procedures, all the way from routine hematology testing to exotic genetic sequencing of, for example, an HIV isolate. Sponsors often utilize centralized laboratories for routine samples in clinical trials, a measure that not only ensures standardization of analysis procedures but also simplifies the statistical calculations at the end of the trial. Even if local laboratories are used for something as straightforward as determining hemoglobin and hematocrit levels in patients treated with recombinant human erythropoietin, care must be taken to ensure that data from all laboratories conform to the same analytical standards.

A closely analogous, but more complex, situation arises when the clinical end point relies upon a diagnostic parameter that includes human interpretation and, inevitably, a subjective component: histology, vascular imaging, electrocardiography, computerized tomography, and the like. In such situations, the most efficient and reliable route to standardization is the use of a centralized reading panel. In a study of cervical dysplasia treatment, three expert gynecologic pathologists were impaneled to read initial and final biopsy slides from all patients at all sites, thus ensuring that the same interpretive criteria were universally applied.

Managing Clinical Supplies

Integrity of clinical supplies is critical. In a blinded trial, poor labeling of clinical supplies can lead to the substitution of one dosage strength for another – completely confounding trial results and costing the sponsor significant loss of time and money. In another example, a delay in supplying some sites with -20 degree C freezers could result in unrecognized temperature-induced drug inactivation, an event whose effect on trial results would be disastrous.

Managing Biological Specimens

Just as management of clinical supplies ensures integrity of what goes into the patient, management of biological specimens does the same for what comes out of the patient – and may be critical to operational success of the trial. For example, in a first-in-man trial of a viral vector, a living biological agent with potential therapeutic effects, critical blood level data could be obtained only by culturing the vector from serum samples. Mishandling of the blood, by exposing it to heat or ultraviolet light, could inactivate the virus and render it nonviable on culture. Should such an event occur, an artifact induced by poor ex vivo study procedures would be misinterpreted as absent blood levels – severely skewing the interpretation of the 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:

1. THE CLINICAL TRIAL PROTOCOL GUIDE
2. CLINICAL DEVELOPMENT PLAN GUIDE
3. THE PROSPECTIVE PATIENT PACKAGE INSERT

To receive a copy of the guide(s), visit the Contact Us page or 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

BioStrategics Consulting Ltd provides a range of management-level clinical development consulting services to the pharmaceutical, biotechnology and medical device industries, including: Clinical development strategy and management, conceptualization, implementation, and management of Phase 1, Phase 2, first-in-man, and proof-of principle clinical trials, IND planning and preparation, FDA and other regulatory authority submissions, meetings, and related interactions, Clinical strategic planning for small molecules, biotechnology products, immunotherapeutic agents, novel drug delivery technologies, and medical devices in virtually all therapeutic areas, New technology assessment, due diligence, and program planning, Clinical development advisory services to senior-level management (CEO, COO, CSO, BOD).

Copyright © 2011 BioStrategics Consulting Ltd.

When we consider operational success, there are two distinct aspects: Getting the Right Data and Getting the Data Right. The first concerns site selection, standardized clinical assessments, centralized lab procedures, management of clinical supplies and management of biological specimens. The second concerns case report form design, clinical monitoring, data entry and management, statistical programming and analysis, and quality assurance.

This week I would like to discuss Getting the Right Data, and specifically clinical trial site selection.

Site Selection Considerations

Getting the right data starts with the clinicians who enroll, treat and evaluate the clinical trial patients. When choosing clinical trial sites, there are a number of factors that require careful consideration (see below), but first and foremost should always be the sites ability to gather high quality data. This broad statement encompasses the experience and qualifications of the site staff, the availability of suitable patients who meet the protocol entry criteria, and the ability to perform the required clinical assessments.

CONSIDERATIONS IN SITE SELECTION

• Experience and qualifications of the investigator
• Experience and qualifications of study coordinator and other staff
• Availability of suitable patient population
• Availability of specialized diagnostic or therapeutic equipment
• Track record with previous, similar trials
• Academic or “thought leader” credentials
• Geographic location (including international)
• Anticipated rate of patient accrual
• Timing of Institutional Review Board meetings
• Contractual and budgetary negotiations
• Regulatory history (FDA audits, “blacklist”)

Site selection requires due diligence on the part of the sponsor to ensure that the proposed clinical trial site meets all the considerations listed above. One of the most important decisions the sponsor makes when embarking on a new clinical trial is the choice of the principal investigator. It goes without saying that the principal investigator should be experienced and qualified in the disease area, but also in the running, coordination and leading clinical studies. The role is not an easy one, and requires the individual to be both tough on fellow investigators and available to help think through the myriad of challenges that arise during a clinical study. It is also customary for the principal investigator to play a key role in recruiting patients, analyzing data, publishing the results and speaking at conferences.

One area that requires careful attention in the site selection considerations is that of the anticipated rate of patient accrual or recruitment. It is this author’s experience that every clinical trial center over estimates the number of patients they can recruit in a given time. One simple method one can utilize to assess the ability of a clinical trial center to recruit a specific number of patients that meet the protocol entry criteria over a given period is to perform a retrospective review of their patients to determine the actual number of patients that meet the inclusion and exclusion criteria of the protocol over a several month period. This is usually a reasonable estimate of what the center can actually recruit. If, on the other hand, significant advertising of the clinical study is planned, then it is possible that the recruitment could be a little higher than the historical trend.

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:

• THE CLINICAL TRIAL PROTOCOL GUIDE
• 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

BioStrategics Consulting Ltd provides a range of management-level clinical development consulting services to the pharmaceutical, biotechnology and medical device industries, including: Clinical development strategy and management, conceptualization, implementation, and management of Phase 1, Phase 2, first-in-man, and proof-of principle clinical trials, IND planning and preparation, FDA and other regulatory authority submissions, meetings, and related interactions, Clinical strategic planning for small molecules, biotechnology products, immunotherapeutic agents, novel drug delivery technologies, and medical devices in virtually all therapeutic areas, New technology assessment, due diligence, and program planning, Clinical development advisory services to senior-level management (CEO, COO, CSO, BOD).

Copyright © 2011 BioStrategics Consulting Ltd.

This week I would like to discuss certain considerations around clinical trial sample size in defining a successful clinical trial protocol.

Sample size for early stage clinical studies that are not out to prove statistically-relevant efficacy tend to be smaller in size, although the larger the number of patients that meet the criteria of the market population one hopes to treat, the great the likelihood that one will generate data that will be predictive of a later stage larger or pivotal study. In deciding the size of an early stage trial, it is important to remember that there should be a reason for every patient included in the study. Early stage trials are often exploratory or pilot in nature to test feasibility, define a dose range, and/or help identify the appropriate methods to measure changes and differences.

It is typical in dose-response studies, to ascertain a dose at which the drug may be used, to enroll several patients at each dose before escalating to the next in the hope of identifying any side effects or adverse events that would define the upper limit of the dose range. Similarly, in early efficacy-indicating studies, one would prefer to include as many patients as possible at doses likely to be used commercially to observe the variation and level of effectiveness of the drug using as many assessment criteria as possible.

For later stage and larger clinical trials, the sample size must be large enough to minimize the possibilities of false-positive or false-negative trial results, but not so large as to overwhelm the team’s logistical capabilities or extend the timelines beyond reason. Consultation with a biostatistician is essential to balance these factors and determine the mathematically most efficient sample size that will allow the trial to meet its primary objectives. Important factors that are considered in determining sample size include:

One of the biggest problems I have observed in later stage studies designed to demonstrate the efficacy of a drug in comparison to the current standard of care is the tendency to under size the study by overestimating the efficacy of the drug and underestimating the efficacy of the standard of care. Great care should be taken also from overemphasizing what is seen in early stage uncontrolled studies where bias can creep in and overestimate the potential of the new drug.

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.

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.

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.

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.