Regulating and monitoring clinical trials has become an increasingly complex and challenging business for the Food and Drug Administration and other government agencies that fund and oversee biomedical research. There are more clinical studies in the United States and abroad, many involving multiple sites, complex study designs, and more research participants. Many studies deal with complex biotech therapies, medical devices, and combination products and call for greater participation of vulnerable subjects, including children. 

Efforts to better manage the flood of data from these research programs is generating a number of electronic record keeping and processing methods and systems that, in turn, require new rules. These developments impose new challenges for IRBs and research institutions, which continue to evolve to meet new requirements. 

To cope with these developments, FDA has launched an initiative to update its Human Subject Protection and Bioresearch Monitoring (HSP/BIMO) program to reflect this larger, more decentralized global research enterprise. Announced by Deputy Commissioner for Operations Janet Woodcock in June [View from Washington, August 2006], the project aims to safeguard study participants and ensure that trials produce high-quality data, while also bolstering public confidence in clinical research activities and in FDA's oversight. 

An HSP/BIMO steering committee headed by Woodcock has established working groups to tackle key issues, which include: 					

Updating inspection and compliance policies to establish a more risk-based approach to selecting research sites for inspection and better defining what constitutes quality clinical data.

Revising investigator disqualification procedures to facilitate the removal of unethical researchers more quickly while ensuring due process.

Clarifying adverse event reporting policies to help IRBs deal with the overwhelming volume of adverse event reports they now receive and advising investigators more clearly on what information has to be filed.

Revising FDA's internal governance of BIMO programs across centers to establish a more unified system.

Finalizing a proposed rule for ensuring that sponsors maintain ethical standards in foreign clinical studies not conducted under IND rules.

Linda Tollefson, FDA assistant commissioner for science and deputy director of the Office of Science and Health Coordination, who reports to FDA Associate Commissioner for Science Norris Alderson, now is more involved in the BIMO initiative as the acting director of FDA's Good Clinical Practice Program. Tollefson also directs FDA's Offices of Women's Health and Orphan Product Development and chairs the agency's internal IRB, which oversees human subject research conducted by FDA scientists. 

David Lepay, who has headed the Good Clinical Practice Program (GCPP) for the past decade, remains a special assistant to Alderson, but now is working out of FDA's San Diego office and focusing more attention on international clinical research policy and programs. A main project for Lepay has been to develop a final rule on FDA acceptance of data from foreign clinical trials, which is moving through the review process. Lepay is also involved with efforts to extend harmonized standards on good clinical practices (GCPs) beyond the United States, Europe, and Japan as a way to achieve common oversight approaches in the developing world. To this end, Lepay is working with the World Health Organization and conducting educational programs in Asia and South America on research ethics policies and practices. 

Lepay also seeks to finish a number of FDA guidances and policies under development at FDA. In recent months, the agency has issued guidance documents on IRB registration, use of data monitoring committees, and dealing with falsification of information and exceptions from informed consent for emergency research. In addition to a final rule on foreign clinical data, Lepay is involved with updating policies to assure the integrity of clinical information in computerized data systems and on reporting adverse events to IRBs. 

Meanwhile, Tollefson seeks to strengthen the GCCP operation. In addition to Lepay moving to the West Coast, his long-time deputy Stan Woollen retired from the agency. A new addition to the program is biophysicist Jean Toth-Allen, who comes from the Center for Devices and Radiological Health (CDRH) where she was involved with its BIMO program for devices. Patricia Block, Bonnie Lee, and Carolyn Hommel complete the GCPP staff.  

GCCP's small size requires it to collaborate with other FDA science and policy offices. Lepay's work on international research issues involves him more directly with the Office of International Activities and Strategic Initiatives headed by FDA Deputy Commissioner Murray (Mac) Lumpkin. One growing component of Lumpkin's office is the Office of Pediatric Therapeutics, which recently added ethicist Robert (Skip) Nelson to its staff. Nelson is responsible for providing guidance and advice related to pediatric clinical trial conduct and design, as required by Congress; he replaces Sara Goldkind, who has become more involved in the Critical Path and BIMO initiatives. 

FDA's efforts to update clinical trial oversight and policies fit with its broader campaign to spur the development of more innovative treatments under its Critical Path Initiative. To this end, the Center for Drug Evaluation and Research (CDER) established a new Office of Translational Sciences (OTS) last May (2006) to coordinate CPI activities and other cross-cutting science initiatives. This new "super office" headed by Shirley Murphy provides a new home for important drug review activities: the Office of Clinical Pharmacology headed by Larry Lesko and the Office of Biostatistics under Robert O'Neill. These offices review data on applications while also playing a central role in encouraging the development of new biomarkers for clinical research and adaptive trial designs. 

OTS provides a focal point for launching and tracking what FDA officials hope will be a growing number of Critical Path collaborative efforts. Agency leaders set the stage for moving forward in this area by unveiling the Critical Path Opportunities List last March, which outlines 76 projects that could speed the pace of turning biomedical discoveries into new therapies. Since then, FDA has announced several new consortia for developing predictive biomarkers plus efforts to develop new statistical approaches and designs for trials. 

The formation of OTS was part of a larger CDER reorganization to also address concerns about drug safety. CDER Director Steven Galson established the Office of Surveillance and Epidemiology (OSE) headed by Gerald Dal Pan, former director of CDER's Office of Drug Safety. OSE has three divisions for drug risk evaluation; surveillance, research, and communications support; and medication errors and technical support. 

At the same time, Paul Seligman, who formerly directed this operation, moved up to head a new Safety Policy and Communication Staff directly under Galson. Seligman's office oversees FDA's Drug Safety Oversight Board and MedWatch program for reporting adverse events to the agency. 

A related change was to shift the Division of Scientific Investigations (DSI) out of Bob Temple's Office of Medical Policy and back into its former slot in the Office of Compliance, now headed by Deborah Autor. Joseph Salewski has been acting director of DSI since the departure of Joanne Rhoades several months ago. 

CDER efforts to address public concerns about drug safety reflect continued pressure on clinical research sponsors for more data transparency. Researchers, patient advocates, and policy makers are demanding broader disclosure of trial results, including failed studies. Patient and disease organizations also seek more timely and accurate trial listings, putting pressure on pharma companies to post more study information on 

A related campaign is to require pharma companies to complete promised postapproval studies. Industry's poor record in this area has generated considerable criticism, and new mandates for listing trials and disclosing results are being discussed as part of drug safety legislation slated for public consideration next year.  

Articles

View from Washington

A changing research enterprise requires clearer policies and more effective regulatory tactics.

FDA Updates Oversight, Encourages Innovation

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

This was the first full year of the European Union's revised medicines legislation, which came into force late in 2005. New legal provisions gave the European Medicines Agency in London responsibility for evaluating generic and biosimilar medicines, "compassionate use" medicines, medicines for use outside the EU, and "core dossier" applications for pandemic-influenza vaccines. All new medicines for HIV/Aids, cancer, diabetes, neurodegenerative disorders, and "orphan" diseases now have to be submitted through the centralized authorization procedure.  

Statistics compiled early in 2006 showed that 43 initial marketing authorization applications for new medicines for human use were received by the agency in 2005—slightly up from the 40 in 2004. During 2006, a sharper upward trend led to forecasts of 62 applications for all of 2006, rising to a likely 79 in 2007, boosted in part by the emergence of the first "biosimilars"—in effect, generics of biological products. Demands for orphan status remained strong, with 77 requests for official designation in just the first nine months of 2006.  

The EU regulation on pediatric medicines completed its legislative process during the year, and the agency is now making plans to establish in 2007 the new Paediatric Committee, which will provide opinions on Paediatric Investigation Plans, plus coordinating a pediatric research network and providing information on pediatric clinical trials. 

As a result, the workload is expected to continue to increase. In addition, from the beginning of 2007 the EU will grow again, from its current 25 member states to 27, with the accession of Bulgaria and Romania. So while the EMEA's budget already rose to x123.6 million in 2006, up from the 2005 figure of x111.8 million, further increases are expected for 2007, along with additional staff.

Transparency became a hot topic in 2006—partly in response to more general moves within the EU to open up increasingly to public scrutiny. During the year the agency published extensive information on withdrawals of applications for authorization, and agreed to publish many of its own meeting agendas and minutes. Mechanisms to prevent conflicts of interest—principally wider requirements on disclosure—were also extended in a bid to provide reassurance on impartiality and independence among regulatory agencies. 

As part of this trend, 2006 also saw the introduction of a new framework for developing relations with the agency's stakeholders, focusing in particular on patient, consumer, and health care professional organizations and on the provision of information about medicines to the public. This has led to increased interaction with patient and consumer groups. As can be seen from the accompanying table, the agency's management board now includes representatives of patient groups and medical organizations. 

The first meeting took place of the EU Pharmaceutical Forum, a high-level group of ministers from the 25 member states, raising some slender hopes of improved conditions for the stimulation of research and development in Europe. One small improvement in the general European context since 2005 is that there is a growing consensus on the merits of a vigorous European pharmaceutical industry. But there is still little sign of consensus over how to sustain it, with pressures increasing from health care financing agencies for ever-tougher cost–benefit assessments of medicines. 

The year was punctuated by repeated warnings from the research-based industry—and the clinical trials community—over the risk that Europe was becoming steadily less attractive as a base. Part of the argument is economic: Pricing regimes in Europe remain tough in many member states, and widespread parallel importing continues to erode industry revenues. But part of the argument relates more to the climate for investment, research, and enterprise in Europe.  

Locators

Along with the titles and phone numbers of personnel, View from Brussels columnist Peter O'Donnell gives an update on the regulatory front in Europe.

European Regulatory Agencies Update

 The process by which medications reach the blood stream when administered other than intravenously, for example, through nasal membranes. 

 An official communication from FDA to an NDA sponsor announcing an agency decision. 

See also approval letter, approvable letter, not-approvable letter.

 Denotes an event when an eClinical trial system is enabled for capturing data, usually used for EDC systems where devices are not shipped to users. 

 Basis for selecting target population for a clinical trial. Subjects must be screened to ensure that their characteristics match a list of admission criteria and that none of their characteristics match any single one of the exclusion criteria set up for the study. 

See also inclusion criteria, exclusion criteria.

 Any noxious and unintended response associated with the use of a drug in humans. 1. Post-approval: an adverse event that occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function. 2. Pre-approval: an adverse event that occurs at any dose and where a causal relationship is at least a reasonable possibility. NOTE: FDA 21CFR 310.305 defines an adverse drug experience to include any adverse event, "whether or not considered to be drug-related". CDISC recognizes that current usage incorporates the concept of causality. [WHO technical Report 498(1972); ICH E2A]  

 Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. NOTE: For further information, see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. "[Modified from ICH E2A]" 

Synonyms: side effect, adverse experience. See also serious adverse event, serious adverse experience.

 Step-by-step procedure for solving a mathematical problem; also used to describe step-by-step procedures for making a series of choices among alternative decisions to reach a calculated result or decision.  

 The likelihood that a relationship observed between 2 variables is due to chance. The prob-ability of a Type 1 error. [Modified from AMA Manual of Style]  

 A written description of a change(s) to, or formal clarification of, a protocol.     

American National Standards Institute (ANSI).

 Founded in 1918, ANSI itself does not develop standards. ANSI's roles include serving as the coordinator for U.S. voluntary standards efforts, acting as the approval body to recognize documents developed by other national organizations as American National Standards, acting as the U.S. representative in international and regional standards efforts, and serving as a clearinghouse for national and international standards development information. [HL7]  			

 A set of subjects whose data are to be included in the main analyses. This should be defined in the statistical section of the protocol.   NOTE: There are a number of potential analysis sets, including, for example the set based upon the Intent-to-treat principle. [ICH E9]   

 Variables used to test the statistical hypotheses identified in the protocol and analysis plan; variables to be analyzed. [PR Project] 

 A small application, typically downloaded from a server.   

 1. Computer application: software designed to fill specific needs of a user; for example, software for navigation, project management, or process control. 2. Regulatory application: Application made to a health authority to investigate, market, or license a new product or indication. 

Synonyms: 1. computer application, application software.

 An official communication from FDA to an NDA/BLA sponsor that lists issues to be resolved before an approval can be issued. [Modified from 21 CFR 314.3; Guidance to Industry and FDA Staff (10/08/2003)]   

approval (in relation to institutional review boards).

 The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, good clinical practice (GCP), and the applicable regulatory requirements. [ICH E6]  

 An official communication from FDA to inform an applicant of a decision to allow commercial marketing consistent with conditions of approval. [Modified from 21 CFR 314.3; Guidance to Industry and FDA Staff (10/08/2003)]   

 A planned sequence of elements, typically equivalent to a treatment group. [SDTM] 

 A measurement, evaluation or judgment for a study variable pertaining to the status of a subject. NOTE: Assessments are usually measured at a certain time, and usually are not compounded significantly by combining several simultaneous measurements to form a derived assessment (e.g., BMI) or a result of statistical analysis. 

 the term assessment is intended to invoke some degree of evaluation or judgment concerning subject status.    

 A systematic and independent examination of trial-related activities and documents to determine whether the evaluated trial-related activities were conducted, and the data were recorded, analyzed, and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory requirement(s). [ICH E6 

 Document that certifies that an audit has taken place (at an investigative site, CRO, or clinical research department of a pharmaceutical company). [ICH E6 

 A written evaluation by the auditor of the results of the audit.   [Modified from ICH E6 

 1. Documentation that allows reconstruction of the course of events. 2. A secure, time-stamped record that allows reconstruction of the course of events relating to the creation, modification, and deletion of an electronic study record. [1. ICH E6 

 Information pertinent to the understanding of a protocol. NOTE: Examples include investigator brochure, literature review, history, rationale, or other documentation that places a study in context or presents critical features. [PR Project]  

 Trial in which a particular type of subject is equally represented in each study group. 

 An indicator of the throughput (speed) of data flow on a transmission path; the width of the range of frequencies on which a transmission medium carries electronic signals. All digital and analog signal channels have a bandwidth.  

 Assessment of subjects as they enter a trial and before they receive any treatment.  

  Demographic, clinical, and other data collected for each participant at the beginning of the trial before the intervention is administered. NOTE: Randomized, controlled trials aim to compare groups of participants that differ only with respect to the intervention (treatment). Although proper random assignment prevents selection bias, it does not guarantee that the groups are equivalent at baseline. Any differences in baseline characteristics are, however, the result of chance rather than bias. The study groups should be compared at baseline for important demographic and clinical characteristics. Baseline data may be especially valuable when the outcome measure can also be measured at the start of the trial. [CONSORT Statement]    

 Systematic error in creating intervention groups, such that they differ with respect to prognosis. That is, the groups differ in measured or unmeasured baseline characteristics because of the way participants were selected or assigned.  NOTE: Also used to mean that the participants are not representative of the population of all possible participants. [ICH E9]   

 Approaches to data analysis that provide a posterior probability distribution for some parameter (e.g., treatment effect), derived from the observed data and a prior probability distribution for the parameter. The posterior distribution is then used as the basis for statistical inference. [ICH E9 

 Statistical approach named for Thomas Bayes (1701–1761) that has among its features giving a subjective interpretation to probability, accepting the idea that it is possible to talk about the probability of hypotheses being true and of parameters having particular values.    

 Probability of showing no significant difference when a true difference exists; a false acceptance of the null hypothesis. 

 Situation or condition that causes a result to depart from the true value in a consistent direction. Bias refers to defects in study design or measurement. [AMA Manual of Style; see also ICH E9, CONSORT Statement] 

 Methods for quantitative measurement of a drug, drug metabolites, or chemicals in biological fluids.    

 Rate and extent to which a drug is absorbed or is otherwise available to the treatment site in the body.    

 Scientific basis on which drugs with the same active ingredient(s) are compared. NOTE: To be considered bioequivalent, the bioavailability of two products must not differ significantly when the two products are given in studies at the same dosage under similar conditions.    

 An application to FDA for a license to market a new biologic product in the United States. 

 A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. [Biomarker definitions working group]  

 Branch of statistics applied to the analysis of biological phenomena.    

 Checking and assessing data prior to breaking the blind, for the purpose of finalizing the planned analysis. [Modified ICH E9]  

  Products that appear identical in size, shape, color, flavor, and other attributes to make it very difficult for subjects and investigators (or anyone assessing the outcome) to determine which medication is being administered.    

 A study in which the subject, the investigator, or anyone assessing the outcome is unaware of the treatment assignment(s). NOTE: Blinding is used to reduce the potential for bias. [Modified ICH E6 

See also blinding/masking, double-blind study, single-blind study, triple-blind study; contrast with open-label or unblinded study.

Preventing identification of treatments/procedures/test to test subjects or study personnel results in order to limit bias (e.g., open-label; single-blind; double-blind). NOTE: Blinding is a procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Includes further distinction between single- and double-blind. Masking, while often used synonymously with blinding, is usually associated with concealing the specific study intervention used. [ICH E9] The term "masking" is often preferred in the field of ophthalmology. [AMA Manual of Style] 

Glossaries

This newly updated glossary includes even more terms relevant to clinical trials professionals.

CDISC Clinical Research Glossary, Version 5.0

Drug development companies face one of the toughest operating environments: Clinical research costs continue to rise steadily at a rate of 12%–14% annually; average development and regulatory cycle times are worsening; the volume and scope of clinical research activity is increasing while the volume of approved new drug applications and drug development success rates remain low. 

Development resources in the current climate will be further constrained by market conditions for prescription pharmaceuticals: Public trust in industry integrity has eroded sharply; drug detailing and advertising practices face increasing scrutiny; charges against FDA effectiveness loom as potential openings to overhaul the agency; and the changing of the guard in both houses of Congress threatens to intensify branded drug pricing practices and the use of generic drugs.  

Today's operating realities underscore the importance of speed and efficiency as central to all viable drug development strategies. In doing so, companies optimize product revenue while minimizing development costs. The rewards for speed and efficiency can be great with an average of $30 million in out-of-pocket development costs saved and $1.1 billion in incremental prescription revenue gained for each product. A company's aggressive and ongoing pursuit of speed and efficiency also delivers other benefits, including streamlined and continuously improved development operations and coordinated organizational support. 

A select group of companies stand apart as the fastest drug developers—"Speed Demons"—during 2000 to 2005. Bayer, Astra-Zeneca, Allergan, Boehringer-Ingelheim, and Merck are the five fastest, and they appear resistant to some of the challenges that plague most biopharmaceutical companies at this time. Speed Demon companies are almost always the fastest among those with which they compete. They exhibit far less cycle-time variability while maintaining levels of development spending comparable to industry benchmarks. 

Whereas most biopharmaceutical companies saw their development and regulatory cycle times increase between 2000 and 2005, for example, Speed Demons defied convention and shortened their development and regulatory timelines. During that six-year period, the fastest 10 companies reduced their median development speed by 20% (from 66.5 to 53 months) and held regulatory cycle times flat. Between 2000 and 2005, the typical company saw median development cycle times increase by 3% and regulatory cycle times increase by nearly 11%. 

In each therapeutic area where they compete, the fastest development companies beat median development and regulatory cycle times more than 83% of the time, demonstrating that speed and efficiency are not chance or haphazard events. In addition, the fastest drug developers managed to minimize development and regulatory cycle-time variability, suggesting that they are implementing speed and efficiency strategies across their portfolios. 

In comparison, the slowest companies display high levels of variability, suggesting that examples of efficient drug development practices may be found and applied within their own organizations. 

Between 2000 and 2005 the fastest development companies delivered as much as a 17-month development speed advantage over average performers and as much as a three-month regulatory speed advantage. So what are the fastest companies doing? Interviews with executives from the fastest companies suggest a number of common practices centered around leveraging resources and collaborations: 					

They collaborate more actively with global regulatory agencies.

They use eClinical data management technologies consistently and widely.

Fastest companies, for example, terminate 56% of their discontinued projects in Phase I, whereas slowest companies terminate only one-third of discontinued projects in that time frame. And drug companies that have higher relative CRO usage report completing their projects closer to projected time frames and submitting their projects more than one month closer to projected submission dates.  

Faster submissions in the absence of faster approvals are a hollow achievement. But this is not the case with Speed Demons. They tend to have shorter regulatory approval times. The industry median regulatory review time (i.e., NDA submission to NDA approval) was 15.7 months during 2000 to 2005. In that same period, the fastest companies received approval in a median of 13 months.  

Speed Demon practices are not rooted in leading-edge and proprietary technologies, nor are they the result of radical approaches to managing and conducting clinical studies. The fastest drug developers attribute their success to superior and consistent implementation of concepts supported across the organization. 

It is difficult for companies to sustain a speed advantage for extended periods due in part to the uncertainties of major portfolio changes, significant financial and operating challenges, and merger and acquisition disruptions. Only two of the current fastest companies—Merck and Astra-Zeneca—were ranked among the five fastest during the previous six-year period. 

Between 1995 and 2000 the fastest drug developers were Zeneca (now AstraZeneca), GlaxoWellcome (now GlaxoSmithKline), Merck, Pfizer, and Abbott. Key practices cited by Speed Demon companies during this earlier time period appear more insular, focusing on project team empowerment, project planning effectiveness, and data management effectiveness. In the more recent period evaluated, Speed Demon practices focus to a large extent on managing the effectiveness of external collaborations. 

Several practices are frequently cited by today's Speed Demons as areas that may yield speed advantages in the future. In interviews, the fastest companies revealed that they are focusing on improving study conduct efficiency. They cite reducing protocol design complexity, applying new approaches to recruiting and retaining patients, and implementing better investigative site management practices as essential new improvement opportunities.   

Development and regulatory cycle time reductions are not single occurrences. They are based on identifiable practices best employed by Speed Demon companies that can be learned, imitated, and implemented by all sponsor companies. By shortening overall cycle times, the fastest drug developers are lowering their direct development costs and extending product sales within an intensely competitive and challenging operating environment.  

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

Clinical Trial Insights

Generalizing fastest drug development strategies and practices.

Hitching a Ride with the Speed Demons of Drug Development

Websites, along with print and broadcast advertisements, are commonly used by investigators and institutions to recruit research subjects. In some cases, the information provided on these Websites may constitute the earliest components of the informed consent process. 

In May 2002, the HHS Office of Inspector General (OIG) issued a report, 

Clinical Trial Websites: A Promising Tool to Foster Informed Consent

. The OIG report recommended that OHRP: 					

Provide further guidance to IRBs on clinical trial Websites.

Clarify that risk and benefit information in trial listings is subject to IRB review and approval.

Require IRB review of any prescreening used for specific trials.

"Current guidance does not require IRB review if the clinical trial listing is limited to the following basic trial information: title, purpose of the study, protocol summary, basic eligibility criteria, study site location(s), and how to contact the study site for further information. This is a sound policy that we do not propose to change. However, some Websites we reviewed provide more than the prescribed basic trial information mentioned in current guidance. In these instances it is unclear to IRBs whether review of the listing is required."  

The OIG report also recommended that the review of pre-screening activities should address any relevant privacy and confidentiality issues. 

HHS regulations at 45 CFR 46.109(b) require that IRBs ensure that information given to subjects as part of informed consent meets the requirements specified in the regulations at 45 CFR 46.116.  

Except as provided elsewhere in this policy, no investigator may involve a human being as a subject in research covered by this policy unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence. 

    The HHS regulations also state at 46.111(a)(4) that, among other requirements, an IRB must determine that informed consent will be sought from each prospective subject or the subject's legally authorized representative, in accordance with, and to the extent required by HHS regulations at 46.116. The IRB may require that information, in addition to that specifically mentioned in 46.116, be given to the subjects when in the IRB's judgment the information would meaningfully add to the protection of the rights and welfare of subjects (46.109(b)). 

The regulations at 45 CFR 46.116(a) and (b) list the informational requirements for informed consent. 

One method of recruiting subjects is through advertisements (e.g., posted notices and newspaper or magazine advertisements, Websites). OHRP consistently has interpreted HHS regulations to provide IRB authority and responsibility for review of study recruitment material, including advertisements. Although Websites use a different medium than traditional print or broadcast advertisements the requirements are the same.  

When Is IRB Review of Clinical Trial Websites Required?

When information posted on a clinical trial website goes beyond directory listings with basic descriptive information, such information is considered part of the informed consent process and therefore requires IRB review and approval. Basic descriptive information includes: 									

how to contact the study site for further information. 

Information exceeding such basic listing information includes descriptions of clinical trial risks and potential benefits, or solicitation of identifiable information. 

What Points Should IRBs Consider When Reviewing Clinical Trial Websites, if Appropriate?

As with the review of all recruitment materials, IRBs should pay particular attention to risk and potential benefit information to ensure it is presented in a balanced and fair manner. The information presented should not mislead, for example, by promising benefits or implying a benefit beyond that potentially provided by the research. 

IRBs reviewing clinical trial Websites also should assess the types of incentives, if any, that are being offered to prospective subjects. Monetary and non-monetary incentives (e.g., access to services or programs) can create undue influence on a potential subject's decision about research participation. IRBs must ensure that the clinical trial Website makes clear that participation in a trial is voluntary, and that incentives for participation are not so great that they compromise a prospective subject's assessment of the risks or affect the voluntariness of his or her choices. 

Some clinical trial Websites ask viewers to answer questions regarding eligibility for a specific clinical trial. If identifiable private information is collected via the clinical trial Website, the IRB should review plans for protecting the confidentiality of that information. The IRB should ensure that the Website clearly explains how identifiable private information might be used. 

Informed consent must be obtained for the collection of any information about the respondent unless the IRB has determined that the informed consent requirement can be waived. There are only two circumstances under which the regulations give IRBs authority to waive the requirements for obtaining informed consent.  

The first IRB waiver authority is applicable only to research activities designed to study certain aspects of state or local public benefit or service programs; the conditions under which this waiver may be authorized by an IRB are detailed at 45 CFR 46.116(c).  

The second IRB waiver authority is described in the HHS regulations at 45 CFR 46.116(d) as follows:  

An IRB may approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent set forth in this section, or waive the requirements to obtain informed consent provided the IRB finds and documents that:  

				1) the research involves no more than minimal risk to the subjects;			

				2) the waiver or alteration will not adversely affect the rights and welfare of the subjects; 			

				3) the research could not practicably be carried out without the waiver or alteration; and			

4) whenever appropriate, the subjects will be provided with additional pertinent information after participation.  

(Note that research involving children as subjects requires parental permission and child assent unless waived (46.408).) 

When Is IRB Review of Clinical Trial Websites Not Required?

Clinical trial Websites that provide only directory listings with basic descriptive information about clinical trials in general (as listed above) do not need to be reviewed by an IRB. Examples of clinical trial listing services that do not need IRB review and approval include the National Institutes of Health (NIH) 

 Website, the NIH National Cancer Institute's cancer clinical trials listing (Physician Data Query [PDQ]), and the government-sponsored AIDS Clinical Trials Information Service (ACTIS). 

If you have specific questions about how to apply this guidance, please contact OHRP by phone at (866) 447-4777 (toll-free within the United States) or (240) 453-6900, or by email at 

Resources

This document from HHS and OHRP provides IRBs with instructions for reviewing trial information listed on Websites.

Guidance on Institutional Review Board Review of Clinical Trial Websites

				Office for Human Research Protection 

Deputy Director and Director, Office of International Activities

Director, Division of Compliance Oversight

Director, Division of Education and Development

Director, Division of Policy and Assurances

				Irene Stith-Coleman (240) 453-8138			

				Andrew von Eschenbach*  (301) 827-3310			

Deputy Commissioner for International and Special Programs

Chief Staff Officer and Associate Commissioner for Legislation

Senior Associate Commissioner for Policy,  Planning

Associate Commissioner for Science and Health Coordination

Assistant Commissioner for Science and Deputy Director, Office of Science & Health Coordination

Associate Commissioner for External Relations

				Jason Brodsky      (301) 827-6251  			

Associate Commissioner for Management and Chief Financial Officer

Assistant Commissioner for Counterterrorism Policy

Assistant Commissioner for International Programs

Assistant Commissioner for Women's Health

Washington editor Jill Wechsler provides an updated list of U.S. regulatory agency personnel.

U.S. Departments and Offices

  American Association for the Advancement of Science 

  American Association of Blood Banks 			

  Abbreviated Antibiotic Drug Application (FDA) (used primarily for generics) 			

  Association of American Medical Colleges 			

  American Association of Pharmaceutical Scientists 			

  Association of the British Pharmaceutical Industry 			

  American College of Clinical Pharmacology 			

  Association for Clinical Data Management (UK)			

  A national trade association representing independent, commercial scientific, and engineering firms 			

 Association of Clinical Pharmacology Units 			

  Associate Commissioner for Regulatory Affairs (FDA) 			

  Association of Clinical Research Professionals (formerly Associates in Clinical Pharmacology, ACP)			

  Changed its name to ICR–Institute of Clinical Research (UK) 			

  Alcohol, Drug Abuse, and Mental Health Administration (no longer exists) 			

  Adverse Drug Event; Adverse Drug Effect 			

  absorption, distribution, metabolism, and excretion (used to describe pharmacokinetic processes) 			

  ADROIT Electronically Generated Information Service, a subscription service that provides subscribing organizations with access to adverse drug reaction data from the Medicines Control Agency's ADROIT (Adverse Drug Reaction On-line Information Tracking) database  			

  Adverse Event Reporting System (FDA) 			

  American Federation for Medical Research, formerly the American Federation for Clinical Research (AFCR) 			

  Agency for Health Care Policy Research (NIH) 			

  Association of Independent Clinical Research Contractors (UK) 			

  acquired immune deficiency syndrome, acquired immunodeficiency syndrome  			

  attributable, legible, contemporaneous, original, accurate (dimensions of data integrity)			

ante meridian, morning (12:00 midnight thru 11:59:59) 

  American Foundation for AIDS Research 			

  Arzneimittelgesetz (German Drug Law) 			

  American Medical Writers Association 			

  Abbreviated New Drug Application (for a generic drug) 			

 American National Standards Institute 			

  Association of Official Analytical Chemists 			

  Association Pharmaceutique Belge (Belgium) 			

These translations help make sense of initials commonly used by clinical researchers around the world.

Applied Clinical Trials-12-01-2006