Protocol

• Consent: The IRB verifies that the informed consent form (ICF) is

S understandable to the subject population, S embodies the "Elements of Informed Consent" as stated in the U.S. Code of Federal Regulations [18] and the ICH E6 Good Clinical Practice: Consolidated Guideline [19], and S that an institutionally acceptable statement regarding the privacy of "protected health information" is incorporated (HIPAA compliance).

• Investigator brochure.

• Periodic safety report from the investigator and the company.

• Advertisements: The IRB also confirms that any compensation being offered to study participants is not coercive and that any advertising is not false or misleading.

In addition, the IRB has an ongoing safety oversight responsibility, both through review of adverse experiences through IND safety reports (which must be forwarded to the IRB by the principal investigator) and review of periodic reports by the principal investigator. The IRB also remains available to evaluate any complaints from subjects, which may arise in relation to their participation in the study.

Most IRBs are associated with hospitals or academic institutions. "Commercial" IRBs, also frequently referred to as "central" IRBs, also exist. These are duly constituted IRBs that operate as a service business offering review of clinical research. It is important to note that hospital, academic, and commercial IRBs are held to the same requirements under U.S. federal regulations and ICH GCP guidelines. In general, academic investigators are required to have their research approved by their institution's IRB. Some nonacademic hospitals may also require that research done by medical staff be approved by the hospital's IRB. In general, however, outpatient and multicenter studies conducted by nonacademic investigators may be reviewed and approved by a commercial IRB. Use of a single commercial IRB for review and approval of a multicenter study can yield substantial economies in effort, money, and time [11, 12].

In response to the need for ongoing independent monitoring of data from certain large and prolonged blinded studies of a variety of medical interventions in serious or life-threatening diseases, a role has developed for the data monitoring committee (DMC) also known as a data safety monitoring committee (DSMC) or data monitoring board (DMB) (Fig. 8.22) [20]. DMCs are discussed in a draft FDA Guidance (fda.gov/cder/ guidance/index.htm). DMCs usually consist of individuals with the expertise in one or more of the disciplines of clinical medicine, medical specialties in question, preclinical science, clinical trials methodology and administration, biostatistics, and medical ethics. Sponsors may be represented but do not participate in meetings in which unblinded data are reviewed. DMCs periodically review data from a study, including

- Also known as a Data Monitoring Committee (DMC). These committees have developed in response to the need for ongoing independent monitoring of data from large and prolonged studies, typically in seriousor life-threatening diseases.

' Membership usually consists of experts in one or more disciplines (clinical medicine, pre-clinical science, clinical trial methodology, or medical ethics).

k Different and separate from an IRB.

- Examples include the safety concerns related to cardiovascular events for several NSAIDs.

k Studies can be stopped for unexpected adverse events or substantial efficacy during study conduct, usually at predetermined points.

Fig. 8.22. Data Safety Monitoring Committee unblinded data as appropriate, from the perspective of whether safety issues, or clear failure of efficacy, or clear superiority of efficacy may warrant the premature termination of the study or modification of the conditions of the study. Of note, recent safety concerns relating to cardiovascular events for several NSAIDs were identified in large postapproval clinical trials by use of DMCs, as noted, for example, in Pfizer's statement on Celebrex [21].

It is important to recognize that while certain oversight activities of the IRB and DMC may appear to overlap, the role of the two entities is distinct. All human research requires IRB approval. The IRB discharges a broad set of responsibilities on behalf of the subject, only one of which is ongoing review of safety information, which is normally blinded. A DMC, on the other hand, is determined to be warranted for individual studies on a case by case basis and is chartered to periodically review data, usually unblinded, in order to provide the sponsor with recommendations regarding continuation with no changes, continuation with modifications, or premature termination of the clinical trial. If periodic checks of data are needed, for example for safety, such interim assessments need to be built into the statistical analysis of studies and formally described in methods, as they will impact the sample size calculations.

In the modern era of conducting clinical trials, computers have become an essential tool for completing the work. Word processors, database systems, statistical programs, scanning systems, and others are commonly used (Fig. 8.23). Therefore, it is essential that computer or information technology (IT) support is available throughout the process. The conduct of clinical trials will generate a large amount of data that is used to answer the questions for which the trials were designed. The data collected will come from a variety of sources and be of many diverse types including, for example, physical exams, laboratory analysis results from blood and urine samples, pathology reports, patient demographics, drug blood levels, drug records, patient or caregiver questionnaires, r Computers have become essential tool in the modern era *

of conducting clinical trials:

o Word processing r o Databases o Statistical programs r o Pharmacokinetic programs o Scanning systems r IT support is essential throughout the clinical trial.

r Clinical trials generate large amount of data that come from many sources that must be collected in simple formats so coders can translate it into computer language.

Responsible for ensuring quality of data generated from clinical trials.

CDM works closely with IT, statisticians, clinical research, & regulatory.

Responsibilities include: o Data entry o CRF development c Programming c Data cleanup

Data entry is process wherein data is put electronically into database:

o Entry from paper CRFs, o Transfer from one electronic source to another (e.g., scanned data or electronically captured data [EDC]). r Programming and data cleanup:

o Programming is required to build edit checks used to clean or scrub data. Data is checked for errors with aid of computer checks.

c Data cleanup and corrections to data documented for clear trail if audited.

r IT personnel collaborate closely with statisticians, clinical research, data management, and regulatory.

Fig. 8.23. Information Technology Support clinical tests (e.g., blood pressure), hospital/clinic charges, x-rays, electrocardiograms, and others. These all need to be collected in a simple format so coders can translate it into computer language. Case report form design needs input from IT groups. Some reports can be scanned directly into the database. Electronic data collection can be done directly at sites, but it requires proper training of site staff and is expensive for the equipment and setup. The data across all studies, which may cover 4-8 years and be thousands of records and CRFs, must be collected and entered into the database so it may all be pooled as necessary when the NDA is being prepared. One example of this is all of the safety data that will need to be pooled across all relevant studies for completing the NDA and package insert. With the technology expanding at a rapid rate as it has, making data consistent over a 4-8 year period of time can be a real challenge. IT personnel work very closely with the statisticians as would be expected. They also work with clinical research, data management, and regulatory within clinical operations but are involved in nonclinical areas. Some examples where IT support is needed include preclinical studies (e.g., toxicology and carcinogenicity) and computational chemistry (designing new drugs).

Clinical data management is responsible for ensuring the quality of the data obtained from the clinical trial (Fig. 8.24). As the name implies, this function is responsible for managing the data. This role will include formatting the data so it may be easily accessed when performing the appropriate statistical tests. Data management personnel will work closely with IT, statisticians, clinical, and regulatory during the clinical development program. Specific responsibilities within this group would include data entry, CRF development, programming, and data cleanup.

Data entry is the process by which the data is placed electronically into a system. This may include the entry of data from paper CRFs or the transfer of electronic data from scanned data or electronically captured data. Because the entry of data into one location from all clinical trials is essen-

Fig. 8.24. Clinical Data Management tial to ensuring efficiency as the development program continues, it is important that clinical data management personnel are involved in the development of the CRF or the means used to collect the data (e.g., scanned CRFs or electronic data capture devices). For example, many clinical trials will require the collection of blood and urine for laboratory analyses. Many laboratories have the capability to report the results of the analyses in an electronic format. It is important to know that the sponsor of the IND has a system in place to accurately receive these data into its database. Furthermore, there will be a considerable amount of programming required to format the data received into a consistent and manageable format for further statistical analysis. Programming will be required to build a set of edit checks (described further below), which will be used to clean or scrub the data that has been collected from a clinical trial.

A large, time-consuming, and interactive responsibility of clinical data management is the process of data cleanup. Clinical trials will involve the collection of a large volume of information. For example, a single CRF (one patient) in a clinical trial may involve 20,000 fields of data. Therefore, a trial involving 100 patients will generate 2,000,000 pieces of data. It is highly likely that errors will have been made in the collection of this data even with the amount of on-site monitoring and training that has taken place. Many of the data fields collected can be checked for errors with the aid of computer checks (edit checks). An example is with blood pressure data. It is common to build programmed checks in which the entered data is checked against specific blood pressure criteria to identify possible errors that may exist. One type of edit check may read, "identify all systolic blood pressures (SBP) over 200 mmHg." This check would be run against all SBP data and the computer would identify all those patients and times that SBP was over 200. The entire collection of edit checks is run against the database several times until no further data is "kicked out" or identified. All data that is identified by an edit check is provided to the clinical team members responsible for the particular study sites so the data may be clarified and corrected as needed. Documentation of all corrections or explanation for no changes is required so that a clean trail is left should an audit be conducted in the future.

Once the clinical trial is completed, the results will need to be documented in an integrated clinical study and statistical final report (Fig. 8.25). These reports are the core documents for the NDA/BLA/CTD. The ICH E3 guideline provides the guidance for the format and contents of this report. In general, the format of the report will be as listed in Figure 8.25 [22].

An author of both the clinical and statistical reports will need to be identified early in the clinical trial. The lead author for the clinical report is the company's clinical leader for the product and project who often wrote the protocol as well, with significant collaboration with the lead biostatisti-cian and input from clinical managers and principal investigators. The protocol and statistical report are the two source documents for the clinical report. It is not uncommon to turn over the responsibility for completing the report to a medical writer (often a separate function) who is responsible for managing the entire writing process. There is a considerable amount of material that must be incorporated into a final report, and much of it can be inserted from other sources. For example, many sections of the protocol can be pulled directly into the final report. As tables and figures are generated and the data is analyzed, new analyses and tables or figures may be necessary to more accurately demonstrate an important finding.

In our experience, it requires a minimum of 3 months and frequently more time after the end of a study to complete the integrated clinical and statistical final report. Much of this time is spent on entering the remaining data from the study, cleaning up the data, generating the final tables and figures, analyzing the results, authoring the report, and getting its review and approval. The report goes through a review process within the sponsoring company. The key questions are manifold: is the data reported clearly in tables and text?; is there data and information missing?; is the writing style scientifically sound and good English?; are the efficacy and safety summaries representative of the data?; are the design features adequately addressed to place qualifiers (limits) on the summaries?; does the data support the conclusions and recommendations? A key activity subsequent to finalization of the integrated report is publication in independent, refereed medical journals. Here the principal investigators lead the effort and work more proactively with the company's biostatisticians and clinical leaders to write the papers.

Clinical trials historically have been carried out outside of a sponsor's "home country" (i.e., "global clinical research") for a variety of reasons (Fig. 8.26). Many large pharmaceutical/biotech companies are now global operations in their basic research, research alliances, clinical research, and marketing of products. A measure of success (both research and marketing) for these companies now is the simultaneous approvals and launch of a product around the world. Cost-effective operations on a global scale include the following advantages: less demanding requirements for a Clinical Trial Application (the equivalent of an IND), less cost per patient, access to worldwide expert investigators, and access to more patients faster. In addition, "registration trials," which use local opinion leaders as investigators in multicenter trials, have frequently been used to facilitate drug approval in individual countries.

k Once clinical trial is completed, results must be reported in two parallel & linked final study reports (statistical and clinical reports).

k ICH E3 guideline provides guidance for format & contents for authors.

k In general, format contains following sections:

k ICH E3 guideline provides guidance for format & contents for authors.

k In general, format contains following sections:

o

Introduction

o

Study objectives

o

Investigational plan

o

Study patients

o

Efficacy evaluation

o

Safety evaluation

o

Discussion and overall conclusions

o

Tables and figures

o

Reference list

o

Appendices

k Typically requires timeframe of minimum of 3 months to complete (often longer) after study has ended.

k Typically requires timeframe of minimum of 3 months to complete (often longer) after study has ended.

r Clinical trials have been conducted outside the US for a variety of reasons including:

c Less demanding requirements for a Clinical Trial Application (equivalent to an IND).

e Less cost.

o Access to expert investigators.

c Access to patients.

o To complete "registration trials" that utilize local opinion leaders to facilitate drug approval in individual countries.

r Drug development today is often carried out on a global scale:

c High standards and GCP for grant of approval in multiple countries.

c It is more feasible with ICH initiative.

c It reduces costs associated with drug development.

Clinical product development is carried out on a global scale today. In past years, a separate development program might have been carried out in each of many different national environments. It is now generally accepted that a single development program conducted to a high and GCP compliant standard, with portions of it carried out in a number of different countries, will provide a basis for approval in multiple countries. The impetus for a single development program was initially economic, driven by the recognition that as clinical research became more complex, costly, and time consuming, carrying out a set of duplicative local development programs was unaffordable. As the International Conference on Harmonization initiative has progressed and as European drug regulation has become centralized, the single development program has become more feasible. The U.S. FDA embraces the ICH initiative and accepts international studies for U.S. approvals.

Sponsors conducting clinical research outside of their home country, at least in the industrialized world, can today reasonably expect that good clinical practice compliance is achievable and that, with appropriate study management, data from any study will be acceptable for multinational use. A practical consideration in international studies is the language challenges such that a consent form and case report form will need translation into the country's primary language; some English words or phrases may translate different meanings.

The overall budget for the clinical development of a product, including all studies and operations at the company and with outside resources (investigators and CROs), is usually about one-half of the total drug development budget (Fig. 8.27). The Tufts Center for the Study of Drug Development calculated this cost to be $450 million out of $802 million in 2001 [23]. An individual study may cost a company $250,000 to $5 million or much more depending on its size, duration, and complexity. Fig. 8.27 lists some of the internal and external budget considerations. Clinical operations consumes the k Investigator Site Costs: o PI / Co-I salaries c Coordinator salary c Lab fees c IRB fees C; Drug control fees c Special procedure fees o Overhead (25%-65%) r Overall Cost Variables:

c Size of study (number of patients) c Duration of study c Complexity of design c Sophistication of design r Costs to Sites: o Per Patient: $5,000 - $15,000 c 1,000 patient trial: $10 MM

r Company Costs:

o Investigator training & meetings o Patient enrollment o Site and CRF Monitoring o Auditing of sites o Drug Formulation, Manufacturing

& Distribution o Data management (CRFs) o Report writing & Publications o Medical staff oversight o CRO expenses o Safety reporting c Regulatory affairs & FDA filings o Overhead r Overall Product Costs:

o Total: $900 MM - $1 B per drug o Clinical: 50% = $450 MM

largest portion of the overall budget, because of its labor intensive requirements, such as monitoring staff and visits, medical staff involvement and oversight, and protocol and report writing. CROs may consume a large portion of the budget, as companies may send out portions of work in the clinical area to absorb the major increases of work over specific time periods, especially to gear up for the large phase 3 trials, plus a CRO can perform patient assignment, statistical analyses, and more. As noted earlier, millions of data pieces are collected and need to be entered into databases and related work, which the CDM group performs. Drug has to be prepared in blinded fashion for the company and comparator groups. Safety data must be collected and analyzed on a continual basis keeping the medical safety group very busy. Basically, each department involved in any way in clinical research adds to the cost of clinical development.

The sites, where the studies are done, and their investigators have a budget for a list of work and services that they provide, for which examples are provided in this slide as well. The cost per patient and per site again depends on the size, duration, and complexity of the work for the site and may be influenced by other factors as well. An individual study budget can be very expensive. For example, as noted in the figure, a study involving 100 patients can cost $500,000.00 to $1.5 million to conduct. However some studies may be much larger. For example, some cardiovascular studies may involve 5,000 patients costing as much as $50 million. The institution or hospital may pass along patient care charges to the company, of course for any added work by the patient care staff for the study. Institutional overhead is demanded by institutions and is highly variable, often with universities demanding higher fees similar to government contracts, which have overhead as high as 50-75%.

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