Policy and Medicine

Specialty Societies and Patient Advocates Contribution to Comparative Effectiveness Research

A recently article in Health Affairs explained how, “Specialty societies and patient advocates have critical roles to play to help accelerate the benefits of comparative effectiveness research (CER).” 

Specialty societies are a “trusted intermediary that can convey the views of practicing physicians to those sponsoring and conducting research, disseminate research findings widely and effectively, and foster conversations about the research and its importance between patients and physicians.” 

Patient advocates can explain the importance of CER to their constituents, helping to address fears that some may have that CER is a tool to deny needed care.  They can also disseminate specific findings to educate patients about the sorts of interventions they should (and should not) request. 

The authors of the article suggest ten specific steps that specialty societies and patient advocates can take to promote the use of CER. 

The authors include include Norman Kahn, MD, Executive Vice-president and Chief Executive Officer of the Council of Medical Specialty Societies (CMSS); John Rother, JD President and CEO of the National Coalition on Health Care; Timothy Lynch, JD, Director of Foundation Programs for the ABIM Foundation; David Hoyt, MD, Executive Director of the American College of Surgeons; and Steven Weinberger, MD, Executive Vice President and Chief Executive Officer of the American College of Physicians.

The Research

Specialty societies and patient advocates should urge the Patient-Centered Outcomes Research Institute (PCORI) and other entities sponsoring CER to ensure patients and clinicians play active roles in designing CER studies and identifying the research questions to be studied. 

Studies should be designed to inform the real-world decisions physicians and patients must make, and including clinicians and informed patients in the design process would help.  Societies could help train clinicians to participate effectively in the CER process, and advocates could train patients, who are often concerned about outcomes—such as those related to quality of life—that may not be apparent to researchers or clinicians.

Specialty societies and patient advocates should help ensure that reports produced by the researchers undertaking CER studies are written to maximize their value for physicians and patients. 

Societies and patient advocates should review those reports and provide feedback to PCORI about their usefulness and suggested improvements.  Similarly, societies and advocates could seek out opportunities to review reports conducted outside of PCORI.

Specialty societies and patient advocates should support complete transparency in CER.  Societies and patient advocates should call for information about research methods, investigators’ affiliations, and funding sources to be detailed explicitly and disseminated with the findings.

Access/Dissemination

Specialty societies should incorporate CER findings as quickly as possible into practice guidelines, patient guides, and other educational and communication tools.  To maximize the usefulness of CER studies for clinicians and patients, specialty societies should respond quickly to new research, disseminating findings through their journals, continuing medical education (CME) offerings, and educational programs that meet the standards of specialty certifying boards for inclusion in maintenance of certification.  Patient advocates should also disseminate evidence-based research findings through their communication channels.

Specialty societies and patient advocates should advocate for decision support tools that incorporate guidelines reflecting CER findings.  Societies and patient advocates should work with the Office of the National Coordinator for Health Information Technology (ONC) and the HIT vendor and policy communities to ensure that systems and templates for electronic health records can accommodate the incorporation of guidelines reflecting CER findings, and can capture and deliver the data and information that are needed.

Physician-Patient Communication

Specialty societies should educate their members about how to talk to their patients about evidence-based medicine, emphasizing the importance of fully disclosing risks and benefits discovered in the research, and describing all viable treatment options.  Physician communication should also elicit patients’ concerns, preferences, and values.  Patient advocates should educate their constituents about the importance and validity of CER, describing how it can help advance more personalized care.  Doctors are uniquely positioned to persuade patients, most of whom have little experience as consumers or users of research or statistical evidence, of the value and integrity of CER findings.  However, many physicians could benefit from advice about how to talk about CER findings and their relevance to patients.  Specialty societies are well-suited to provide that assistance, and they should work collaboratively with patient advocates to develop communications strategies to reinforce the benefits of CER in improving care and address concerns that CER will lead to the denial of needed care.

Specialty societies and patient advocates should promote shared decision-making, including the use of decision aids that incorporate CER findings.  Societies and patient advocates can help promote the use of existing decision aids and  encourage the development of new ones.  Societies can also encourage physicians to welcome dialogue and empower their patients to become genuine partners in their care by encouraging discussion and questions about their care.

Measurement

Specialty societies and patient advocates should encourage measure developers to develop measures that are based on proven evidence.  As producers of guidelines that underlie measures, and as consumers of measures, specialty societies can enhance their quality both through basing guidelines on CER analyses and by urging the prompt development and updating of measures as the research base matures.  Patient advocates can promote patient experience measures and public reporting derived from measures reflecting evidence-based clinical guidelines.

As specialty societies build and expand registries, they should link CER and other evidence bases in order to optimally answer clinical questions.  Specialty societies are increasingly employing registries to identify and close gaps in quality of care, reduce wasteful and inefficient care variations, and implement quality improvement measures.  These registries’ power to shape care will be enhanced if they collect the categories of data that would be most useful to CER researchers.  Specialty societies and patient advocates should seek to support these linkages through future specifications for physician quality reporting system (PQRS) registries, meaningful use criteria, and electronic health record (EHR) certification standards.

Promoting CER

Specialty societies and patient advocates should encourage their constituents to communicate the benefits of CER within the medical and patient communities and among the public.  The practice of medicine and the health of the American people will be improved if CER can deliver on its promise, and physicians and engaged patients can be CER’s most effective ambassadors.  Physicians and patient leaders can publicly embrace CER and explain how it can improve health care quality and advance personalized care.

FDA Draft Guidance - Oversight of Clinical Investigations: A Risk Based Approach to Monitoring

 
The Food and Drug Administration (FDA) announced the publication of a draft guidance titled, “Oversight of Clinical Investigations: A Risk Based Approach to Monitoring.”  This is the first time since 1988 that the agency issued a specific guidance document on how a study sponsor may meet its obligation to monitor or oversee the conduct of a clinical study. 

The guidance is intended to assist sponsors of clinical investigations in developing risk-based monitoring strategies and plans for investigational studies of medical products, including human drug and biological products, medical devices, and combinations thereof. The overarching goal of the guidance is to enhance human subject protection and the quality of clinical trial data.

The guidance describes strategies for monitoring activities that reflect a modern, risk-based approach that focuses on critical study parameters and relies on a combination of monitoring activities to oversee a study effectively. For example, the guidance specifically encourages greater use of centralized monitoring methods where appropriate.

A summary from the FDA Law Blog noted that the draft guidance encourages the use of centralized monitoring, i.e., remote evaluation of study data at a location other than the site where the study is being conducted.  The extent to which remote or centralized monitoring is used should depend on the complexity of the study and the electronic accessibility of study data.  According to the guidance, centralized monitoring should:

• include activities that can be done as well or better remotely (e.g., standard checks for consistency and completeness of data);
• target on-site monitoring by identifying higher risk clinical sites;
• perform monitoring activities that can only be done in a centralized manner (e.g., statistical analyses to identify data trends);
• identify missing or inconsistent data and potential protocol violations;
• verify source data remotely, where both source data and CRFs can be accessed remotely;
• analyze site characteristics (e.g., high screen failure or protocol violation rates and delays in reporting data);
• complete administrative tasks such as collecting regulatory documents.
• For each clinical trial, FDA recommends that the sponsor develop a monitoring plan that describes:
• the monitoring approaches and procedures to be used;
• communicating monitoring results;
• managing noncompliance, including developing specific processes for investigating suspected data falsification;
• training and study-specific information, including training monitors and study site staff.

A full summary of the draft guidance appears below. Comments and suggestions regarding this draft document should be submitted by November 28, 2011. Submit comments to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov. All comments should be identified with Docket No. FDA–2011–D–0597.

For questions regarding this draft document, contact (CDER) Ann Meeker O’Connell at 301-796-3150, (CBER) Office of Communication, Outreach and Development at 800-835-4709 or 301-827-1800, or (CDRH) Chrissy Cochran at 301-796-5490.

Background

Sponsors of clinical investigations are required to provide oversight to ensure adequate protection of the rights, welfare, and safety of human subjects and the quality and integrity of the resulting data submitted to FDA. In the past two decades, the number and complexity of clinical trials have grown dramatically. These changes create new challenges in clinical trial oversight such as increased variability in investigator experience, ethical oversight, site infrastructure, treatment choices, standards of health care, and geographic dispersion.

In light of these developments, FDA wishes to encourage more effective monitoring of clinical investigations, to ensure adequate protection of human subjects and the quality and integrity of clinical trial data.

The regulations require sponsors of clinical investigations involving human drugs, biological products, medical devices, and combinations thereof to monitor the conduct and progress of their clinical investigations. The regulations are not specific about how sponsors are to conduct monitoring of clinical investigations and, therefore, are compatible with a range of approaches to monitoring.

FDA conducts on-site inspections of clinical investigators, sponsors, contract research organizations (CRO), and institutional review boards (IRB) to assess the protection and safety of subjects and to validate data submitted in new drug applications (NDAs), biologics license applications (BLAs), and device premarket approval (PMA) applications. However, it is not possible for FDA to conduct on-site assessments of every clinical investigator conducting studies involving FDA-regulated products, and most inspections take place after the study is complete. Thus, effective monitoring by sponsors is critical to the protection of human subjects and the conduct of high-quality studies.

FDA is considering the need for additional guidance describing overarching quality risk management approaches to clinical trial oversight. Quality is a systems property that must be built into an enterprise and cannot be achieved by oversight or monitoring alone.

FDA noted how the term monitoring is used in different ways in the clinical trial context. As a result, for purposes of this guidance, FDA stated that, “monitoring generally refers to the methods used by sponsors of investigational studies, or CROs delegated responsibilities for the conduct of such studies, to oversee the conduct of and reporting of data from clinical investigations, including appropriate investigator supervision of study site staff and third party contractors.”

FDA stated that the primary focus should be on the processes that are critical to protecting human subjects, maintaining the integrity of study data, and compliance with applicable regulations. The findings should be used to correct investigator and site practices that could result in inadequate human subject protection and/or poor data quality.

Current Monitoring Practices

A survey conducted through the Clinical Trials Transformation Initiative (CTTI) indicates that a range of practices has been used to monitor the conduct of clinical trials.

Despite this range of monitoring methods, periodic, frequent visits to each clinical investigator site to evaluate study conduct and review data for each enrolled subject remain the predominant mechanism by which pharmaceutical, biotechnology, and medical device companies monitor the progress of clinical investigations.

For major efficacy trials, companies typically conduct on-site monitoring visits at approximately four- to eight-week intervals, at least partly because of the perception that the frequent on-site monitoring visit model, with 100% verification of all data, is FDA’s preferred way for sponsors to meet their monitoring obligations.

In contrast, academic coordinating centers, cooperative groups, and government organizations use on-site monitoring less extensively. For example, some government agencies and oncology cooperative groups typically visit sites only once every two or three years to qualify/certify clinical study sites9 to ensure they have the resources, training, and safeguards to conduct clinical trials.

FDA also recognizes that data from critical outcome studies (e.g., many National Institutes of Health-sponsored trials, Medical Research Council-sponsored trials in the United Kingdom, International Study of Infarct Survival, and GISSI), which had no regular on-site monitoring and relied largely on centralized and other alternative monitoring methods, have been relied on by regulators and practitioners. These examples demonstrate that use of alternative monitoring approaches should be considered by all sponsors, including commercial sponwhen developing risk-based monitoring strategies and plans.

Other FDA Guidance on Monitoring

FDA provided guidance on monitoring of clinical investigations in 1988. That guidance, which was recently withdrawn, stated that the “most effective way” to monitor an investigation was to “maintain personal contact between the monitor and the investigator throughout the clinical investigation.” At the time the guidance was issued, sponsors had only limited ways to effect meaningful communication with investigators other than through on-site visits.

The 1996 International Conference on Harmonisation (ICH) guidance on good clinical practice (ICH E6) addressed monitoring more recently. ICH E6 provides for flexibility in how trials are monitored, advising sponsors to consider “the objective, purpose, design, complexity, blinding, size, and endpoints of a trial” in determining the extent and nature of monitoring for a given trial. Although the ICH guidance specifically provides for the possibility of reduced, or even no, on-site monitoring, it also makes clear that it would be appropriate only in exceptional circumstances to rely entirely on centralized monitoring.

FDA’s 1998 guidance on Providing Clinical Evidence of Effectiveness for Drug and Biological Products, although not focused on monitoring, also suggests more flexibility in discussing what would be considered acceptable monitoring in the context of data standards for published studies that had little or no on-site monitoring. For example, the 1998 guidance states that FDA will “accept different levels of documentation of data quality as long as the adequacy of the scientific evidence can be assured.”

Section III.B of that guidance describes criteria (e.g. prospective plan to assure data quality) for reliance on data from studies that had alternative approaches to quality control and less intensive on-site monitoring. Additionally, the guidance specifically acknowledges that there are many credible and valuable studies conducted by government or independent groups that had very little on-site monitoring, but have addressed data quality in other ways (e.g., close control of and review of documentation and extensive guidance and planning efforts with investigators).

Rationale for Facilitating Risk-Based Monitoring

Many sponsors have understood these guidances as contributing to the notion that FDA expects sponsors to conduct frequent on-site monitoring and 100% data verification for all trials, regardless of their design and complexity. Because existing and recently withdrawn guidance may not clearly reflect FDA’s current recommendations regarding monitoring practices, FDA recognizes the need to clearly articulate their recognition of the value of alternative approaches to facilitate change in industry’s monitoring practices.

There is a growing consensus that risk-based approaches to monitoring, such as focusing on the most critical data elements, are more likely to ensure subject protection and overall study quality, and will permit sponsors to monitor the conduct of clinical investigations more effectively than routine visits to all clinical sites and 100% data verification. For example, incorporation of centralized monitoring practices, where appropriate, should improve a sponsor’s ability to ensure the quality and integrity of clinical trial data. Several publications suggest that data anomalies (e.g., fraud, including fabrication of data, and other non-random data distributions) may be more readily detected by centralized monitoring techniques than by on-site monitoring.

In addition, source data verification and other activities traditionally performed by on-site monitoring can now often be accomplished remotely, as both trial data and source data typically become part of the central submission. These electronic data capture (EDC) systems are making it possible to implement centralized monitoring methods that can enable decreased reliance on on-site monitoring. The guidance is therefore intended to clarify that risk-based monitoring, including the appropriate use of centralized monitoring and technological advances (e.g., e-mail, webcasts, and online training modules), can meet statutory and regulatory requirements under appropriate circumstances.

Steps FDA is Taking to Facilitate Wider Use of Alternative Monitoring Approaches

• FDA also stated that it is initiating operational measures to ensure that its review, compliance, and other functions reflect this view of monitoring. Specifically, FDA:
• Has withdrawn the 1988 guidance on monitoring of clinical investigations
• Issued this draft guidance encouraging risk-based monitoring approaches, including 174 adoption of alternative monitoring methods
• Will ensure that the bioresearch monitoring compliance program guidance manuals (CPGMs) 176 for sponsors, CROs, and monitors (CPGM 7348.810)24 and for clinical investigators and sponsor-investigators (CPGM 7348.811)25 are compatible with the approaches described in this guidance
• Will ensure that all affected program areas within FDA are aware of the goals and purposes 180 of this guidance and its compatibility with current CPGMs
• Will consider establishing processes within CDER for sponsors to voluntarily and 182 prospectively submit and receive feedback on proposed monitoring plans (see section IV.D.4). Sponsors of IDE studies wishing to solicit feedback on their monitoring procedures prior to the submission of the IDE application may either submit a pre-IDE, or contact CDRH’s Division of Bioresearch Monitoring.

The draft guidance strongly encourages sponsors to tailor monitoring plans to the needs of the trial. FDA recognizes that this draft guidance places greater emphasis on centralized monitoring than was envisioned at the time ICH E6 was finalized. However, FDA considers the approach to monitoring described in this draft guidance as consistent with ICH E6.

FDA believes it is reasonable to conclude that the flexibility described in ICH E6 was intended to permit innovative new approaches to improve the effectiveness of monitoring: notably, the advancement in EDC systems enabling centralized access to both trial and source data and the growing appreciation of the ability of statistical assessments to identify clinical sites that require additional training and/or monitoring. We expect that the pharmaceutical and device industries will, for the foreseeable future, continue to use some amount of on-site monitoring. Therefore, as per ICH E6, the complete absence of on-site monitoring will likely continue to be unusual.

FACTORS THAT INFLUENCE STUDY QUALITY AND INTEGRITY

Although the focus of this guidance is on monitoring the oversight and conduct of, and reporting of data from, clinical investigations, FDA considers monitoring to be just one component of a multi-factor approach to ensuring the quality and integrity of clinical investigations. Many other factors contribute to the quality and integrity of a clinical investigation.

FDA stated that the most important tool for ensuring human subject protection and high-quality data is a well-designed and articulated protocol. A poorly designed or ambiguous protocol or case report form (CRF) may introduce systemic errors that can render a clinical investigation unreliable despite rigorous monitoring. Study-specific training of investigators, other site staff, and monitors also contributes significantly to study quality.

Consequently, FDA made recommendations on how to devise and implement a study-specific monitoring plan as well as how to document monitoring activities. FDA acknowledged that there are limited empirical data to support the utility of the various methods employed to monitor clinical investigations. As a result, the recommendations are based, in part, on FDA’s experience from the review of protocols during the IND/IDE phase, data submitted in pre-approval applications, results of inspections conducted to ensure human subject protection and data integrity, and information obtained from public outreach efforts conducted under the auspices of the CTTI.

GENERAL MONITORING RECOMMENDATIONS

No single approach to monitoring is appropriate or necessary for every clinical trial. FDA recommends that each sponsor design a monitoring plan that is tailored to the specific human subject protection and data integrity risks of the trial. Ordinarily, such a risk-based plan would include a mix of centralized and on-site monitoring practices. The monitoring plan should identify the various methods intended to be used and the rationale for their use.

On-Site Monitoring

On-site monitoring is an in-person evaluation carried out by sponsor personnel or representative(s) at the site(s) at which the clinical investigation is being conducted. On-site monitoring can identify data entry errors (e.g., discrepancies between source records and CRFs) and missing data in source records or CRFs; provide assurance that study documentation exists; assess the familiarity of the site’s study staff with the protocol and required procedures; and assess compliance with the protocol and investigational product accountability.

On-site monitoring can also provide a sense of the quality of the overall conduct of the trial at a site (e.g., attention to detail, thoroughness of study documentation, appropriate delegation of study tasks, and appropriate investigator supervision of site staff performing critical study functions). Therefore, on-site monitoring ordinarily should be devoted to assessing the critical study data and processes and evaluating significant risks and potential site non-compliance identified through other sponsor oversight activities.

Centralized Monitoring

Centralized monitoring is a remote evaluation carried out by sponsor personnel or representatives (e.g., data management personnel, statisticians, or clinical monitors) at a location other than the site(s) at which the clinical investigation is being conducted. Centralized monitoring processes can provide many of the capabilities of on-site monitoring as well as additional capabilities. Centralized monitoring processes should be used to the extent appropriate and feasible to achieve the following:

• Replace on-site monitoring for monitoring activities that can be done as well or better remotely (e.g., standard checks of range, consistency, and completeness of data and checks for unusual distribution of data within and between study sites, such as too little variance)
• Target on-site monitoring by identifying higher risk clinical sites (e.g., sites with data anomalies or a higher frequency of errors, protocol violations, or dropouts relative to other sites)
• Augment on-site monitoring by performing monitoring activities that can only be accomplished using centralized processes (e.g., statistical analyses to identify data trends not easily detected by on-site monitoring)
• Monitor data quality through routine review of submitted data in real-time to identify missing data, inconsistent data, data outliers, and potential protocol deviations that may be indicative of systemic and/or significant errors in data collection and reporting at a site
• Verify source data remotely, provided that both source data and CRFs can be accessed remotely
• Conduct aggregate statistical analyses of study data to identify sites that are outliers relative to others and to evaluate individual subject data for plausibility and completeness
• Conduct analyses of site characteristics, performance metrics (e.g., high screen failure rates, high frequency of eligibility violations, and delays in reporting data), and clinical data to identify trial sites with characteristics correlated with poor performance or noncompliance
• Complete administrative and regulatory tasks (e.g., collecting and archiving regulatory documents).

FDA encourages greater reliance on centralized monitoring practices than has been the case historically, with correspondingly less emphasis on on-site monitoring. The extent to which centralized monitoring practices can be employed will depend to some extent on accessibility of electronic records and EDC systems. Sponsors who plan to rely on centralized monitoring processes should ensure that the processes and expectations for site record keeping, data entry, and reporting are well-defined and ensure timely access to clinical trial data and supporting documentation.

If a sponsor intends to rely heavily on centralized monitoring practices, it may still be advisable to conduct at least one on-site monitoring visit per site, preferably early in the conduct of the study, to evaluate site processes and controls for provision of data and source documents, particularly for trials intended to support marketing applications.

Identify Critical Data and Processes to be Monitored

Sponsors should perform a risk assessment that generally considers:

• The types of data to be collected in a clinical trial
• The specific activities required to collect these data, and
• The range of potential safety and other human subject protection concerns that are inherent to the clinical investigation.

Sponsors should consider the findings of the risk assessment when developing a monitoring plan. A study protocol should clearly identify those procedures and data that are critical to the reliability of the study findings. These generally should include:

• Data that are critical to the reliability of the study findings, specifically those data that support primary and secondary endpoints
• Other data that are critical to subject safety, such as serious adverse events and events leading to discontinuation of treatment
• Processes that underpin subject safety and ethical treatment, such as seeking appropriate  medical consultation or scheduling extra visits in the event of specified clinical or laboratory findings
• Processes that underpin the integrity of these data, such as blinding or referring specified  events for adjudication

A sponsor’s monitoring activities should focus on these critical measurements and on preventing important and likely sources of error in their collection and reporting. When devising an appropriate monitoring plan, the sponsor’s risk assessment should consider the impact and likelihood of error and the extent to which error would be detectable for identified data and processes. The following types of data and processes should ordinarily be subject to more intensive (e.g., higher frequency and more comprehensive) monitoring:

• Conduct and documentation of procedures and assessments related to
• critical study endpoints,
• protocol-required safety assessments, and  
• evaluating, documenting, and reporting serious adverse events and unanticipated adverse device effects, subject deaths, and withdrawals, especially when a withdrawal may be related to an adverse event.
• Adherence to protocol eligibility criteria intended to include only subjects from the targeted study population for whom the test article is most appropriate
• Conduct and documentation of procedures for ensuring that the study blind is maintained, both at the site level and at the sponsor level, as appropriate
• Verification that initial informed consent was obtained appropriately, prior to any study-specific procedures
• Procedures for documenting appropriate accountability and administration of the investigational product (e.g., ensuring the integrity of randomization at the site level, where appropriate)
• Other types of data (e.g., covariate) and processes often may be monitored less intensively and frequently

Factors to Consider when Developing a Monitoring Plan  

A monitoring plan ordinarily should focus on the critical data and processes identified by the risk assessment. The types (e.g., on-site and/or centralized), frequency (e.g., early, for initial assessment and training versus throughout the study), and intensity (e.g., comprehensive (100% data verification) versus targeted or random review of certain data (less than 100% data verification)) of monitoring activities will depend to some extent on a range of factors, considered during the risk assessment, including the following:

Complexity of the study design

More intensive monitoring approaches (e.g., increased frequency of review regardless of the type of monitoring approach selected and/or use of multiple monitoring approaches) may be necessary as study design complexity increases. Examples may include studies with adaptive designs, stratified designs, complex dose titrations, or multiple device placement or unblinded studies.

Types of study endpoints

Endpoints that are more interpretative or subjective may require on-site visits to assess the totality of subject records and to review application of protocol definitions with the clinical investigator. More objective endpoints (e.g., death, hospitalization, or clinical laboratory values and standard measurements) may be more amenable to remote verification. Endpoints for which inappropriate subject withdrawal or lack of follow-up may impede study evaluation are likely to need more intensive monitoring to determine whether follow-up can be improved and to identify the reason(s) subjects are withdrawing.

Clinical complexity of the study population

A study that involves a population that is seriously ill and/or vulnerable may require more intensive on-site monitoring to be sure appropriate protection is being provided.

Geography  

Sites in geographic areas where there are differences in standards of medical practice or subject demographics or there is a less established clinical trial infrastructure may require more intensive monitoring, including some level of on-site monitoring.

Relative experience of the clinical investigator and of the sponsor with the investigator

Investigators who lack significant experience in conducting and overseeing investigations, using a novel or innovative medical device, or with the surgical procedure associated with medical device use may benefit from more intensive monitoring and early mentoring. In addition, the relative experience of a sponsor with the clinical investigator may be a factor in determining an appropriate monitoring plan.

Electronic data capture

Use of EDC systems with the capability to assess quality metrics (e.g., data error rates and protocol violations) in real-time could help identify potentially higher risk sites for the purpose of targeting sites in need of more intensive monitoring (e.g., an on-site monitoring visit).

Relative safety of the investigational product

A study of a product that has significant safety concerns or for which there is no prior experience in human clinical trials (e.g., a phase 1 pharmaceutical investigation or a device feasibility study) may require more intensive monitoring to ensure appropriate investigator oversight of subject safety.

Stage of the study  

A tapered approach to monitoring may be used where appropriate, with more intensive monitoring at initiation and during early stages of a trial. For example, a tapered approach could be used for a complex study where more intensive and on-site monitoring might be required early, but once procedures are established, less intensive monitoring might suffice. Similarly, a tapered approach could be used for relatively inexperienced clinical investigators.

Quantity of data

Some centralized monitoring tools may be more useful as the quantity of data collected increases.

Monitoring Plan

For each clinical trial, the sponsor should develop a monitoring plan that describes the monitoring methods, responsibilities, and requirements for the trial. The plan should provide those involved in monitoring with adequate information to effectively carry out their duties.

All sponsor and CRO personnel who may be involved with monitoring, including those who review and/or determine appropriate action regarding potential issues identified through monitoring, should review the monitoring plan. The components of a monitoring plan might include the following:

Description of Monitoring Approaches

• A description of each monitoring method to be employed during the study and how it will be used to address important risks and ensure the validity of critical data
• Criteria for determining the timing, frequency, and intensity of planned monitoring activities  
• Specific activities required for each monitoring method employed during the study, including reference to required tools, logs, or templates
• Definitions of events or results that trigger changes in planned monitoring activities for a particular clinical investigator.

For example, if it is determined that an investigator deviates significantly from other sites in making safety-related findings or other key safety metrics, the site should be considered for targeted on-site visits. Additional examples of potential triggers include suspected fraud, data outliers (e.g., in rate of enrollment, volume of protocol deviations, or quantity of adverse event/effect reporting), or delays in completing CRFs.

Identification of possible deviations or failures that would be critical to study integrity and how these are to be recorded and reported.

For example, sponsors may wish to establish a specific mechanism for tracking and notifying key study personnel of deviations related to collection or reporting of data necessary to interpret the primary endpoint, regardless of which monitoring method identified a concern.

The study monitoring plan should also describe how various monitoring activities will be documented, regardless of whether conducted on-site or centralized.

Communication of Monitoring Results

• Format, content, timing, and archiving requirements for reports and other documentation of monitoring activities
• Process for appropriate communication
• of routine monitoring results to management and other stakeholders (e.g., CRO and data management),
• of immediate reporting of significant monitoring issues to appropriate personnel, and
• from study management and other stakeholders to monitors.

For example, data management personnel may provide monitors with routine reports of outstanding CRFs or of common data queries at or across sites that may enable effective targeting of monitoring activities.

Management of Noncompliance

Process for addressing unresolved or significant issues (e.g., significant non-compliance with the investigational plan) identified by monitoring, whether at a particular site or across study sites

FDA recommends that sponsors develop and include specific processes for addressing, investigating, and reporting suspected and/or confirmed data falsification.

Processes to ensure that root cause analyses are conducted where important deviations are discovered and that appropriate corrective and preventive actions are implemented to address issues identified by monitoring

Other quality management practices applicable to the clinical investigation (e.g., reference to any other written documents describing appropriate actions regarding non-compliance)

Training and Study-Specific Information

Description of any specific training required for personnel carrying out monitoring activities, including personnel conducting internal data monitoring, statistical monitoring, or other centralized review activities

Training should include principles of clinical investigations, critical protocol-specific requirements, the study monitoring plan, applicable standard operating procedures, and appropriate monitoring techniques.

Planned quality monitoring to ensure that sponsor and CRO staff conduct monitoring activities in accordance with the monitoring plan, applicable regulations, guidance, and sponsor policies, procedures, templates, and other study plans.

For example, many companies have successfully implemented on-site co-monitoring visits (i.e., monitoring visits performed by both a study monitor and the monitor’s supervisor or another evaluator designated by the sponsor or CRO) to evaluate whether monitors are effectively carrying out visit activities, in compliance with the study monitoring plan. These visits may be conducted either for randomly selected monitors or may be targeted to specific monitors, based upon questions arising from review of monitoring visit documentation.

A brief description of the study, its objectives, and the critical data and study procedures, with particular attention to data and procedures that are unusual and require on-site training

A monitoring plan may reference existing policies and procedures (e.g., a standard operating procedure describing issue investigation and resolution). In this case, the sponsor should take appropriate steps to ensure that monitors, whether sponsor or CRO employees, are aware of and are trained on these policies and procedures as well as on the monitoring plan.

CDER intends to evaluate potential processes through which sponsors could voluntarily submit their monitoring plans to the appropriate review division and request feedback from the clinical trial oversight component for the Center.

Monitoring Plan Amendments

Sponsors should consider what events may require review and revision of the monitoring plan and establish processes to permit timely updates where necessary. For example, a protocol amendment, change in the definition of significant protocol deviations, or identification of new risks to study integrity, could result in a change to the monitoring plan.

DOCUMENTING MONITORING ACTIVITIES

Documentation of monitoring activities should include the following:

• The date of the activity and the individual(s) conducting it  
• A summary of the data or activities reviewed
• A description of any noncompliance, potential noncompliance, data irregularities, or other deficiencies identified
• A description of any actions taken, to be taken, and/or recommended, including the person responsible for completing actions and the anticipated date of completion

Monitoring documentation should be provided to appropriate management in a timely manner for review or, as necessary, follow-up.

ADDITIONAL STRATEGIES TO ENSURE STUDY QUALITY

A number of additional steps can be taken to ensure appropriate human subject protection and high data quality.  A fundamental component of ensuring quality monitoring is a sponsor’s compliance with written monitoring plans and any accompanying procedures.

Clinical Investigator Training and Communication

Clinical trial monitors conducting on-site visits have historically played an important role in training the investigator and his/her staff during a study. On-site visits also have served as a primary means of providing feedback to investigators and study personnel on study conduct. Without meaningful training prior to the conduct of a study and of appropriate instruction during the study (e.g., when changes are made to the protocol), investigators and their staff may have difficulty carrying out a trial correctly. Sponsors who plan less frequent or limited on-site monitoring should consider the following:

On-site visits should include sufficient time for mentoring, feedback, and additional training, if needed, during the conduct of the study.

It may be necessary to implement alternative training and communication methods (teleconferences, webcasts, or online training modules) for providing and documenting ongoing, timely training and feedback, as well as to provide notification of significant changes to study conduct or other important information.

Delegation of Monitoring Responsibilities to a CRO

If a sponsor of an IND study delegates the responsibility for ensuring proper monitoring to a CRO, FDA regulations (21 CFR 312.52) require the written transfer of any obligations from a sponsor to a CRO and require the CRO to comply with the regulations. Although sponsors can transfer responsibilities for monitoring to a CRO(s), they retain responsibility for oversight of the work completed by the CRO(s) who assume this responsibility.

Top Clinical Trial Websites

 
A recent post on the blog, Clinical Researchers, provided a wealth of information for health care providers and stakeholders interested in all kinds of research. Specifically, the post provided a reference of 40 useful sites for readers to learn more about clinical trials, as well as sites that include helpful case studies and journals and publications that report results from different areas of clinical research.  The sites are listed below. 

Clinical Trials

Find out more about clinical trials. Learn where the trials are being held, and their purposes. A great reference to different trials happening now, or scheduled to happen in the future.

1. ClinicalTrials.gov: The government puts together information on clinical research trials, including instructions, background and more.
2. Vaxnet.com: A network of clinical trials and research centered around vaccines. Find out more about the latest research in vaccinations.
3. CenterWatch: Resources and information on clinical trials and clinical research. A great, global reference.
4. ClinicalTrials.com: Learn more about different trials available, and what is available. Solid information on clinical research.
5. Clinical Trials: Get information on research currently being conducting throughout the U.S. from the National Institute of Mental Health.
6. Clinical Connection: Learn about different clinical trials, and the research going on right now.
7. Clinical Trials at MD Anderson Cancer Center: Insight into different cancer clinical trials.
8. WHO ICTRP: The World Health Organization includes a look at clinical trials and registration.
9. Clinical Trials at the Mayo Clinic: Find out what clinical research is happening at one of the most prestigious institutions.
10. IFPMA Clinical Trials Portal: Learn more about clinical research, and what sorts of trials are being conduct. Get results as well.
11. Clinical Trials: Duke Health offers information on clinical trials, results and other information that is great to reference.

Some of the best reference materials can be case studies. If you are interested in seeing what has been done in the past, and if you are interested in seeing how different strategies hold up in real world situations, you can visit these clinical case study sites.

1. Clinical Case Studies: Great information, research and reference from Medical Gross Anatomy at the University of Michigan.
2. Clinical Cases and Images: Use this site as a reference for your own clinical research.
3. Case Studies: The Virtual Health Care Team at the University of Missouri-Columbia has a great look at different cases.
4. Case Studies in Science: Great clinical research studies and results that can help you in your own clinical research.
5. Cases: IPLAB.net offers helpful case studies that you can use for reference in your own efforts.
6. Clinical Grand Rounds: Reference these studies from the NIH Clinical Center. Great resources from a respected and reliable source.
7. Case Studies by Subject: A great compilation of clinical research case studies. Plenty to keep you busy with ideas for your own clinical research.
8. CME Cases: Medscape offers you access to great clinical reference points.
9. Clinical Decisions: This reference can help you learn to make better decisions in your clinical settings and research.
10. Challenging Cases: Great, interactive studies that can be used for reference in clinical research.

Journals and Publications Dealing with Clinical Research

Find out more about the latest breakthroughs in clinical research. Get ideas, join the debate, and keep up with the literature. Helpful resources and references.

1. Clinical Trials: This is the Journal of the Society for Clinical Trials. It’s a peer-reviewed journal full of good reference information.
2. Clinical Chemistry: Interesting articles and discussions on clinical research related to chemistry.
3. PubMed: Get access to a number of publications that include clinical research. One of the best reference sites on the Internet.
4. First Clinical: Offers access to different clinical research pubs. A number of options to choose from.
5. Journal Watch: Articles from medical journals around the world, including those related to clinical research.
6. Publications about Clinical Research and Trials: Find out what you need to know about referencing clinical research.
7. Applied Clinical Trials Online: A look at applied clinical trials and research.
8. Journal of Clinical Research & Bioethics: Access to information about clinical research, as well as great references on ethics.
9. Open Access Journal of Clinical Trials: Great journal offering access to articles about clinical trials and research results.
10. JP-CCR: The Journal of Pre-Clinical and Clinical Research is a great reference for researchers around the world.
11. Clinical Medicine & Research: Insightful articles, information, and highlights from current issues. Great reference for what’s the latest in clinical research.

Clinical Research Ethics, Policies and Procedures

Whenever you are involved in clinical research, it is important to understand best practices and have a good idea of ethics. You should be able to learn more about policies and procedures, and learn about what makes for solid, respectable research.

1. Clinical Trials Networks Best Practices: Find out more about best practices in clinical research, getting an idea of patient management, as well as ethics and procedures.
2. Clinical Research Site Training: Get information and training related to running clinical trials and performing research properly.
3. Clinical Trial Ethics: A great resource to help you understand what’s ethical in clinical research.
4. Center for Clinical Research Ethics: This center is a partnership between the Washington University Institute of Clinical and Translational Sciences and the Department of Health Care Ethics at St. Louis University in Missouri. A great reference and resource for anyone interested in clinical research.
5. Clinical Research Policy Analysis and Coordination: A great resource from the Office of Biotechnology Activities at the National Institutes of Health.
6. Clinical Research Ethics Key Function Committee: Find out more about quality assessment of IRB organizations, as well as collaboration ethics and more. A great reference and useful resource.
7. Joint Study Committee on Clinical Research Ethics: Find out more about clinical research ethics, best practices and policies.
8. Research Ethics: Great references and resources related to research, including clinical research.

IOM Clinical Practice Guidelines We Can Trust -- But What About the IOM?

 
The Institute of Medicine (IOM) issued two reports last week “that it said will provide an objective and consistent framework for clinical practice guidelines, and standardize systematic reviews of comparative effectiveness”—also known as comparative effectiveness research (CER). The studies were requested by Congress and sponsored by the Department of Health and Human Services (HHS).

The first report, entitled Clinical Practice Guidelines We Can Trust, includes eight standards and recommendations.

IOM's second report, “Finding What Works in Health Care: Standards for Systematic Reviews,” addresses the “myriad and often competing guidelines for clinical recommendations by offering what it said are 21 standards to ensure objective, transparent, and scientifically valid reviews.”

Background

According to IOM’s press release, “clinical practice guidelines and systematic reviews of the evidence base for health care services are supposed to offer health care providers, patients, and organizations authoritative guidance on the comparable pros and cons of various care options, but too often they are of uncertain or poor quality.  There are no universally accepted standards for developing systematic reviews and clinical practice guidelines, leading to variability in the handling of conflicts of interest, appraisals of evidence, and the rigor of the evaluations.” 

IOM Clinical Practice Guidelines

1. Establishing transparency: The processes by which a clinical practice guideline (CPG) is developed and funded should be detailed explicitly and publicly accessible.

2. Management of conflict of interest (COI): Prior to selection of the Guideline Development Group (GDG), individuals being considered for membership should declare all interests and activities potentially resulting in COI with development group activity, by written disclosure to those convening the GDG.

Disclosure should reflect all current and planned commercial (including services from which a clinician derives a substantial proportion of income), non-commercial, intellectual, institutional, and patient/public activities pertinent to the potential scope of the CPG. Disclosure of COIs within GDG:

• All COI of each GDG member should be reported and discussed by the prospective development group prior to the onset of their work.
• Each panel member should explain how their COI could influence the CPG development process or specific recommendations.

IOM also recommend that members of the GDG should divest themselves of financial investments they or their family members have in, and not participate in marketing activities or advisory boards of, entities whose interests could be affected by CPG recommendations. Additionally, IOM noted that:

• Whenever possible GDG members should not have COI.
• In some circumstances, a GDG may not be able to perform its work without members who have COIs, such as relevant clinical specialists who receive a substantial portion of their incomes from services pertinent to the CPG.
• Members with COIs should represent not more than a minority of the GDG.
• The chair or co-chairs should not be a person(s) with COI.
• Funders should have no role in CPG development.

3. Guideline development group composition: The GDG should be multidisciplinary and balanced, comprising a variety of methodological experts and clinicians, and populations expected to be affected by the CPG. Patient and public involvement should be facilitated by including (at least at the time of clinical question formulation and draft CPG review) a current or former patient and a patient advocate or patient/consumer organization representative in the GDG.

4. Clinical practice guideline–systematic review intersection: CPG developers should use systematic reviews that meet standards set by the IOM’s Committee on Standards for Systematic Reviews of Comparative Effectiveness Research. When systematic reviews are conducted specifically to inform particular guidelines, the GDG and systematic review team should interact regarding the scope, approach, and output of both processes.

5. Establishing evidence foundations for and rating strength of recommendations: For each recommendation, the following should be provided:

• An explanation of the reasoning underlying the recommendation, including:
• A clear description of potential benefits and harms.
• A summary of relevant available evidence(and evidentiary gaps), description of the quality (including applicability), quantity (including completeness), and consistency of the aggregate available evidence.
• An explanation of the part played by values, opinion, theory, and clinical experience in deriving the recommendation.
• A rating of the level of confidence in (certainty regarding) the evidence underpinning the recommendation.
• A rating of the strength of the recommendation in light of the preceding bullets.
• A description and explanation of any differences of opinion regarding the recommendation

6. Articulation of recommendations: Recommendations should be articulated in a standardized form detailing precisely what the recommended action is and under what circumstances it should be performed. Strong recommendations should be worded so that compliance with the recommendation(s) can be evaluated.

7. External review:

• External reviewers should comprise a full spectrum of relevant stakeholders, including scientific and clinical experts, organizations (e.g., health care, specialty societies), agencies (e.g., federal government), patients, and representatives of the public.
• The authorship of external reviews submitted by individuals and/or organizations should be kept confidential unless that protection has been waived by the reviewer(s).
• The GDG should consider all external reviewer comments and keep a written record of the rationale for modifying or not modifying a CPG in response to reviewers’ comments.
• A draft of the CPG at the external review stage or immediately following it (i.e., prior to the final draft) should be made available to the general public for comment. Reasonable notice of impending publication should be provided to interested public stakeholders

8. Updating:

• The CPG publication date, date of pertinent systematic evidence review, and proposed date for future CPG review should be documented in the CPG.
• Literature should be monitored regularly following CPG publication to identify the emergence of new, potentially relevant evidence and to evaluate the continued validity of the CPG.
• CPGs should be updated when new evidence suggests the need for modification of clinically important recommendations. For example, a CPG should be updated if new evidence shows that a recommended intervention causes previously unknown substantial harm, that a new intervention is significantly superior to a previously recommended intervention from an efficacy or harms perspective, or that a recommendation can be applied to new populations.

IOM Standards for Systematic Reviews

In the Medicare Improvement for Patients and Providers Act of 2008, Congress directed the IOM to develop standards for conducting systematic reviews. The recommendations from the second report emphasized similar standards and principles including:

• Manage bias and conflict of interest (COI) of the team conducting the systematic review; and
•  Manage bias and COI for individuals providing input into the systematic review

Discussion

After announcing the two IOM reports, Sheldon Greenfield, MD, executive director, Health Policy Research Institute, University of California, Irvine, and chair of the IOM committee on guidelines, asserted that, “These standards are necessary given that there is little documentation to judge the quality and reliability of many of the existing clinical practice guidelines.”

Dr. Greenfield emphasized that the “Practice guidelines provide valuable data and guidance that not only inform individual decisions about care but ultimately could also improve overall healthcare quality and outcomes.” 

Alfred O. Berg, MD, professor of family medicine, University of Washington School of Medicine, Seattle, and chair of the committee that wrote the report on systematic reviews, noted that, “this report presents the ‘gold standard’ to which those who conduct systematic reviews should aspire to achieve the most reliable and useful products.”

Dr. Berg recommended that the standards in the IOM reports be adopted to “minimize the chances that important health decisions are based on information that may be biased or erroneous.” He did however recognize that doing so, will “take an investment of resources and time to achieve such high standards.”

Commentary

The problem with this report and others like it is the underlining belief system that working with industry to develop and commercialize new therapies is somehow inherently bad and should be managed or eliminated.

The problem with this philosophy is that it fails to recognize expertise and value.  In all other industries working with industry by academicians is considered valuable experience.  But in medicine the ivory tower has decided that they can determine clinical guidelines alone without the input of those who design and work on randomized controlled clinical trials, the backbone of industry-academia collaboration.  

The problem with this is that it is the equivalent of setting a rule that NASCAR drivers should not have any relationships with industry therefore lack the expertise of the latest and best science and drive slower cars but they would be pure.

No patient and I literally mean no patient wants a physician who only has knowledge of old therapies setting “guidelines” for other physicians.     These recommendations if adopted will put us one step closer to “government controlled” healthcare.

Rather than spending all our energy determining eligibility based on relationships with product developers. Would not our time and resources be better spent in finding cures for diseases and coming up with guidelines that implement those therapies?    We have had guidelines for 50+ years and almost all have been out of date within weeks of their release.

The American Surgeon: In Defense of Industry-Physician Relationships

 
As the number of restrictions on physicians working with industry continue to grow, and the places where policies prohibit physicians from collaborating with industry expand, close examination of the reasons supporting these policies is necessary.

The current trend of academic medical centers (AMCs), professional organizations, and States that have begun adopting policies that restrict permissible interactions and activities between industry and physicians dawned shortly after a set of recommendations proposed by Brennan and colleagues in 2006. Examples of the proposed policies placed restrictions on faculty, residents, students, and staff, which prohibited gifts, samples, and several other activities.

One of the main reasons AMCs began to adopt these policies was an attempt to avoid financial conflicts of interest that compromise core values of altruism and fiduciary relationships. In their view, profit motives and financial gains unavoidably introduce bias in medical decision-making and violate public trust. However, there is number of reasons why the adoption of such policies by AMCs is problematic.

Accordingly, a recent editorial by Don K. Nakayama, M.D., M.B.A. Chairman of Department of Surgery at Mercer University School of Medicine, In Defense of Industry-Physician Relationships in the American Surgeon, identified the misperceptions and myths that have led some AMCs and organizations to adopt such restrictive policies on industry interactions.  In his editorial, Dr. Nakayama comes to the “defense of industry-physician relationships” by examining the economic, ethical, and legal foundations for conflict of interest restrictions between physicians and pharmaceutical and medical device industries (“industry”).

One of the first problems with restrictive policies between physicians and industry that Dr. Nakayama identifies is that although some of the regulations themselves grew from alleged and some real conflicts of interest (COI) involving both drug and device trials,  “scientific misconduct, fraud, and dishonesty are noteworthy because of their rarity.” In other words, people overreacted by installing restrictive policies for events that are extremely rare. The problem with this approach was that the policymakers did not consider the other consequences created by such policies that could and are in fact now chilling the collaboration between physicians and industry.

Considering “the vast majority of industry sponsored research results in beneficial drugs and devices of immense benefit,” the potential impact restrictive policies could have on research, development, discovery, education, and patients should have been the first consideration when making restrictions on interactions with industry.

While some restrictions such as payment disclosure is reasonable, making “a total purge of all financial conflicts of interest has become the touchstone of medical professionalism.” This approach is unnecessary. As Dr. Nakayama points out, there needs to be more discussion about “an appropriate middle ground that acknowledges the rights of industry, physicians, residents, medical students, patients, and the public to the benefits that reasonable interactions between industry and physicians may provide.”

By ignoring the rights of these groups, “those who propose restricted industry-physician-patient relationships are thus in conflict with those who recognize a beneficial relationship.” This creates a debate on a number of issues, between those who see industry interactions as a violation of their sense of professionalism versus those who “see restrictions as an affront to their right to determine how they will practice medicine and their own definitions of the ethical practice of medicine.”

Medical Economics

Proponents of COI regulations frequently assert that doctors should have a selfless or altruistic concern for the welfare of their patients absent a financial motive. As Dr. Nakayama recognizes, this approach completely ignores the economic system the US pharmaceutical and device industries operate under, which recognizes that every level of professional interaction between industry and doctors “are necessary as aspects in a robust capitalist economy.”

In a capitalist system, products are developed to generate profits. In the drug and device industry, the process of developing a product is costly, long, and risky. A single drug requires $800 million and 7-12 years or more to come to market, a good chunk of the 18-year duration of patent protection. Only 8 percent of drugs developed become approved drugs. The only way drug and device companies can generate profits is by allocating their resources to either acquire or develop innovative drugs or devices based upon market demand. Society, through government, has recognized that “such innovation is socially desirable and is worth granting industry patent protection on new drugs and devices.”  

To ensure that innovative drugs and devices are effective and safe for the public, government regulations and requirements are complex and rigorous. In fact, even after a product is approved, post-market surveillance is necessary to detect problems that may arise after drug introduction, for which the company remains liable. Consequently, it is precisely because of this balance between high risk, high regulation products that companies “depend on the market for feedback on how to refine their product so that it better fits what doctors and patients need.”

It is also because of this long process of drug development and satisfying regulatory requirements, which limits the period of monopoly pricing power over its product, that companies must allocate resources to bring an approved product to the market through ethically and professionally acceptable marketing and advertising practices. Critics who point to the growing costs of health care claim that profits of the pharmaceutical and medical device sectors are excessive, that the money spent on marketing increases health care costs, and does not primarily serve patient interests.

However, as Dr. Nakayama asserted, “marketing and advertising are not contrary to high quality evidence-based care. They are an integral part of getting any product into the market.” Moreover, those who criticize drug and device companies for advertising easily forget about the numerous hospitals and AMCs who use billboards, commercials, and ads to accomplish the same goals: bring their services to the market.

In addition, by “starting with an unknown drug or device, a company has to overcome established practices of surgeons and physicians.” If the company hopes to recoup any costs for making the product, they have to devote resources to marketing to increase sales and profits, which can be extremely difficult to do when physicians are unfamiliar with their product. Dr. Nakayama gave a perfect example of this: surgeons adopting surgical staples. He explained how this was such a “radical departure of surgical technique, but because of the marketing, advertising, and reinventing the surgery through education, demonstrations and product samples, surgical staples eventually transformed surgery to depend on industry and its surgeon collaborators.

Profit Motive in Industry

The next argument that critics of industry-physician interactions make is that “any benefit that comes to physicians through industry contact is suspect.” They see profit motives and market incentives in medicine as negative challenges to medical professionalism. However, as Dr. Nakayama acknowledges, “the goals of physicians and industry are remarkably congruent and complimentary.”

Both want effective medications and devices that benefit patients. Physicians want them, industry wants to supply them. Doctors want to learn new treatment modalities; industry wants to educate doctors in those techniques and products. Both parties want effective treatments that maximize benefit, minimize harm to the patients, and minimize legal risks. Doctors want to run profitable practices, companies want to run profitable businesses.

The first major area where physicians and surgeons in practice collaborate with industry is in clinical research and trials. Industry depends upon physician researchers with busy clinical practices to test drugs and device and report results. The physicians expose patients to experimental drugs and procedures in the belief that patients will benefit from participation. Neither industry nor physicians want harm to come to study participants but, human testing is risky. That is why such research is strictly regulated and overseen. As such, because physician collaborators are necessary parts of product research and development, they deserve and receive appropriate compensation from industry.

The next area is the vastly larger venue of marketing and sales of drugs and devices after clinical research studies have shown efficacy and safety. Physicians in practice and their patients are the market. Companies need their representatives to interact with medical providers using professional and ethical practices to get their products to doctors and in patient’s hands because of the short period of patent protection to recoup close to $1 billion in product development and testing.   In the end this is a win win scenario as patients benefit from quicker implementation of new and improved therapies. While past practices were occasionally egregious and excessive (i.e. gifts), current industry guidelines prohibit those practices, and help to maintain the highest level of educational activities and contact with industry.

What critics must realize is that the only time industry can have with clinicians’ in busy practices are mealtimes and conferences. However, critics maintain that such contacts “still are tainted by a sense of obligation among physicians to provide a service in return and thus create unprofessional behavior, a sense of entitlement, and demean the profession.” These critics ignore the fact that when industry talks with clinicians about effective novel therapies that have demonstrated safety and efficacy, if a hospital adds it to their formulary or physician adopts it, “the public benefits.”

It is also important for critics to acknowledge the fact that “physicians have the training and sense of professionalism to want the best for their patients and protect them from harm. They have independent sources of information through journals, practice-based learning activities, and professional organizations to confirm or refute industry claims.

As a result, physicians in practice have their professional integrity and the safety of their patients in mind, and are able to filter the message they get in industry marketing.

The Underpinnings of Medical Professionalism

Another concept that underlies prohibitions of COI is that a physician has a fiduciary relationship with the patient. As Dr. Nakayama explained, fiduciary means “someone who acts for and on the behalf of another in circumstances that give rise to a relationship of trust and confidence. One in a fiduciary relationship acts at all times to the benefit of the other, and does not put his or her interests before those of the beneficiary, and thus cannot have a COI with the interests of the beneficiary.” However, Dr. Nakayama argues that a physician-patient relationship does not establish a fiduciary relationship because they are not available to their patients at all times, and the standard of care which doctors adhere are not defined by the maximal benefit to the patient but reasonable standards of the professional practice.

Doctors adhere to professional standards and codes of ethics that they themselves determine as a right of self-government the public has given physicians. The public is able to “retain an interest in professional behavior by physicians through state boards of medicine and a legal system that protects patients from malpractice through the tort law system.” Those groups that want to restrict physicians contact with industry are essentially taking away the rights of doctors to make their own standards and making interactions with industry crimes enforceable by law.

Consequently, instead of using altruism or fiduciary, Dr. Nakayama recommends the business concept of excellent service. He explained that the “tenants of excellent service are putting interest of customers first, integrity to the company’s mission and values, and honesty and ethical business practices. They are directly translatable into medical terms that describe altruism and professional behavior exactly: putting patients’ interest first, scientific clinical integrity and absence of bias in medical decision-making.”

Force of Law

Critics also ignore that physician-industry relationships are protected by the First Amendment of the U.S. Constitution, which guarantees freedom of speech, including the right to market and advertise medical products and drugs. As Dr. Nakayama explained, “it also guarantees freedom of assembly, the right of physicians to meet with industry reps over reasonably priced meals and conferences and to have mutually beneficial contractual relationships with industry to develop new drugs and products. The Copyright and Patent Clause of the First Amendment protects the rights of companies to enjoy monopolistic profits that come to their discoveries under patent protection.”

Dr. Nakayama also acknowledged the fact that industry and professional organizations have themselves developed codes of ethics that guide their interactions. These codes preserve the relationships that are a necessary part of the introduction of necessary drugs to clinical practice, and also minimize and prohibit unethical contacts and activities. Since “part of professionalism is the responsibility to abide by an agreed upon code of ethics without having to resort to the blunt force of law,” there is no need for further restrictions.  

Conclusion

In the end, “across-the-board conflicts of interest restrictions risk the unparalleled advances in medical technology that we enjoy today.” The clear problem with such policies is that they prohibit what are overwhelmingly “productive relationships between industry and physicians that provide novel drugs and devices of immense benefit to society.” Moreover, these policies ignore the fact that “physician researchers and inventors are responsible for an overwhelming array of drugs and staggering list of devices that depend upon industry for product development, production, and marketing.”

The reality is, “industry goals are congruent with those of physicians: patient welfare, safety, and running a profitable business.” Moreover, industry has transformed completely the practice of medicine and surgery. “Its success is measured in the increase in longevity of nearly 10 years from 1950 to the present (68.2 to 77.9 years) and years of productive life. The numbers of employed workers over 65 years have doubled from 1977 to 2007.”

As a result, “humankind owes an overwhelming array of live saving medications and surgical devices to the unique American industry-physician partnership.” Since so many benefits come from relationships between industry and physician, “it is difficult to imagine another system that could create the volume of innovation developed and adopted in the US.” Therefore, if the US continues to restrict industry-physician relationships, Dr. Nakayama asserted that “all of us will suffer.” That is why “preservation of industry-physician relationships is vital to maintain medical innovation and progress.”

Milwaukee Journal Sentinel: The Case of BMP-2 Ignoring Any Benefit from Innovation

 
Progress in medicine is essential for discovering new ways to make people healthier, experience less pain, and to live longer. The efforts of countless researchers, physicians, scientists, and patients have led to tremendous breakthroughs and progress in medicine over the past decade and without their collaboration, it would have been difficult to achieve the quality of life we enjoy today. In fact, without this process, in which drugs and medical devices are made, tested, and updated, we would never find the treatments that eventually help make our lives better.

A recent article from the Journal Sentinel however, undermines this collaboration between researchers, patients, and industry by pointing to a group of physicians involved in a powerful new biological agent that promised to revolutionize back surgery, and suggesting that financial motivations created conflicts of interest.  

The drug in question, known as Infuse, “was like nothing the burgeoning field of spinal fusion surgery had seen before because it turned whatever it touched into bone.” As the Sentinel explained, the “treatment consists of a tapered, metallic fusion cage that looks like a thimble and the BMP-2 bone graft substitute. The substitute, which is placed inside the LT-Cage, includes the genetically engineered human protein (BMP-2) that is placed on an absorbable sponge. The LT-Cage maintains spacing between the vertebrae while the BMP-2 generates the formation of new bone in order to permanently stabilize that section of the spine.”

For the Sentinel, “the story of BMP-2 raised questions about whether doctors should be allowed to do clinical trial research involving products that might enrich them or the company they work for.” What the Sentinel completely ignores are questions about the positive impact BMP-2 has had on patient’s lives, and the benefits enjoyed by patients who chose this treatment over more painful options. This omission is troubling, considering the author himself admits that despite a risk of leaking out, if BMP-2 is properly “confined to the tiny space between vertebrae, it proved as an effective treatment.”

If a treatment is effective, and helps patients, then of what concern should there be about doctors enriching themselves, when patients are benefiting? Shouldn’t their hard work, dedication, investment, and the risks they are taking be adequately rewarded?

The Sentinel examines BMP-2 mainly because of the outcome of an advisory meeting panel in January 2002, which happened prior to the drugs approval. Specifically, the Food and Drug Administration (FDA) panel did not address panel member Stephen Li’s issues with the fact that nine doctors who had a financial stake in the product had test results with it that were nearly twice as good as the doctors who did not have a financial interest.

Consequently, the FDA panel deferred Li’s concerns to Medtronic, the company that was making Infuse. Explaining what happened next, Marybeth Thorsgaard, a spokeswoman for Medtronic clarified that “the company fully disclosed the success rates of the doctors with financial ties to the company to the FDA.” In fact, Markham Luke, chief medical officer in the FDA's device evaluation office, noted that in approving the product, the FDA took into account the conflicts of interest of the investigators.

As a result, with this information in hand, the panel “probed the issue and made its recommendation to the FDA, which ultimately approved the product." FDA also said “the package label for BMP-2 covers all safety concerns that the FDA believes the public needs to know.”

This cooperation thus showed Medtronic’s strong commitment to preventing the promotion of its products for unapproved uses and its implementation of corporate policies and training to prevent that.

Despite the commitment from Medtronic, the Sentinel believes that “the eventual approval of Infuse represented “a familiar playbook,” in which first, a buzz is created about a potential new therapy. As the Sentinel claimed, the next step is for “research - often by doctors with financial ties to the product – to be presented to the FDA for a specific use in a narrow group of people.”

The playbook then is that “once the product is on the market, other uses for it are promoted in articles and presentations, often by doctors with financial ties to the company.” But nothing is illegal about these presentations or articles. In fact, the physicians who provide these service help thousands of physicians across the country learn about new treatments and therapies such as Infuse.

For example, BMP jumped from being used in less than 1% of all fusions in 2002 to being used in 25% in 2006. While the Sentinel claims that much of this increase was fueled by "off-label" use, they also correctly acknowledge that such use is “not illegal for doctors, including those with financial ties to such companies.”

It seems like the issue the Sentinel takes with the use of BMP was that there is “a considerable amount of evidence suggesting that many patients with back pain do just as well over time without” the BMP surgery. Going on this claim, they assert that “spinal fusion is a controversial treatment for degenerative disc disease,” even though they admit it is an “effective treatment.”

One would expect that for a treatment to be classified as controversial, it would have a negative success rate however, the FDA noted when approving the product that “the expected overall success for Infuse is 57.1%.”  So what if fusion without using BMP-2 had a 56.7% success rate? What is the problem with having two treatments effectively treat a particular condition? Why should we be giving patients and doctor’s only one choice?

The reality is, spinal fusion surgery in the past “often required harvesting a small amount of bone from the hip, which can be painful and add time to the surgery.” When BMP was being developed, it held the potential to eliminate that pain and additional time for surgery, and still does.

What the Sentinel is really concerned about is that since the FDA approved the use of BMP for a single-level fusion involving the lumbar spine in which the operation was done from the front, “doctors have been using it off-label in surgical approaches from the back rather than the front, and on the cervical spine as well as the lumbar spine.” To support this claim, the author cites a recent study, which “found a fourfold increase in the use of all BMP products in five years, from 24,000 procedures in 2003 to 103,000 in 2007.”

Of that increase, the study asserted that “about 85% was off-label use.” But as we discussed above, it is not illegal for doctors, including those with financial ties to companies, to prescribe off-label. Accordingly, the fact that BMP has been used off-label increasingly is a positive affect because without its approval, the many uses it is now being used for would still be without effective treatment. It should be noted however, that physicians using BMP for off-label purposes should advise there patients as such.

The Sentinel also takes issue with BMP because despites its approval by FDA, “early concerns about its widespread, unapproved use and adverse reactions in patients have materialized.” The article points to “studies that have warned that it can cause life-threatening swelling in the neck, form bone in unwanted locations and possibly fuel the growth of cancer cells or spark adverse immune system reactions.” But the likelihood or possibility of these risks are not discussed, and are specifically not put into the context of the benefits BMP provides.

Any surgery is going to be risky and expensive, and the fact the surgeons who are conducting these surgeries helped create, study and develop the devices and treatments through industry sponsorship is reassuring. It means that their experience and exposure to the products being used is unmatched.

New Therapy

Consequently, what brought BMP into the media was the fact that Medtronic is now back before the FDA seeking approval for a different BMP-2 product for use in back surgery. The drug, known as Amplify, was considered by an FDA panel last month, in which “concerns about cancer, immune reactions and effectiveness were raised.

Accordingly, the Amplify clinical trial, which involved 463 patients, was completed in 2009. It was noted that of 63 surgeons, twenty-seven who operated on more than half of the patients in the clinical trial had a financial interest in Medtronic at the time of the research. Despite what some feel appears to be a conflict, “Medtronic maintained that because the financially connected surgeons had results that were similar to those who did not have such conflicts, their financial interest in Amplify's success did not affect the results of the trial.”

But the Sentinel still wants to drag Amplify under the bus by suggesting that prominent surgeons, such as Thomas Zdeblick, who helped study BMP-2, have conflicts of interest because of their financial ties to Medtronic. The fact that he holds patent rights to a key component of the product and has received more than $22 million dollars in royalties and other payments from Medtronic since 2002 does not represent a “conflict.” It represents the fair market compensation anyone would expect for the work and dedication he endured to help advance this science.

Just because a physician earns income from his discoveries does not translate that they are somehow unethical as the Sentinel would have one believe.   Inventors of all kinds of products every day wake up with the hope that they are creating something that will help others.  If the products don’t work, people won’t buy them, doctors won’t use them and they won’t get receive income from their failed inventions.  But if they are successful they should reap some reward so they are incentivized to invent the next beneficial product.

Conclusion

Since May of this year, Medtronic joined several drug companies in publicly listing payments to doctors - in advance of federal legislation that mandates such reporting beginning in 2013. Using this list only for purposes of criminalizing the collaboration of physicians with industry, the Sentinel points out only that “several of the doctors on that list are the same ones who wrote articles about the original Infuse clinical trial or who wrote about off-label uses for BMP-2.”

This characterization completely ignores the services and benefits created by the doctors. It does not go to explain the teaching or training impact it has had on other physicians, or the better outcomes and education patients will have when they learn about new treatments. Moreover, the Sentinel does not address the level of transparency and its effect on giving the public a greater sense of trust and integrity in Medtronic for disclosing such payments.

Instead, critics of this kind of collaboration maintain that when information comes from the manufacturers and people who are very vested in the product, the information is tainted, and it creates a conflict. But this claim is misguided.

Collaboration between physicians and industry remains absolutely vital to innovation in the medical technology industry. While some may believe the BMP-2 story highlights doctors being too “cozy” with industry, the reality is, the product is a success story in treating patients with back problems.

Hypertension Treatment Variability Requires Customized Medicine and Continuing Medical Education

 
Three recent studies looking at blood pressure treatment and responses in various population groups, suggest that there is a lot more to hypertension treatment than simple trial and error prescribing.

Hypertension is an unhealthy increase of blood pressure on the arteries. As the Wall Street Journal explained, “the pressure is governed by the body's intricate plumbing mechanism: The heart is the pump, the arteries are the pipes, and the kidneys are sewers that eliminate unwanted fluids. Blood pressure can go up either because there's too much fluid (salt and water) in the system, or because the arteries have narrowed. Blood pressure can rise with a diet that is high in salt.”

What is significant about hypertension is that of the 50 million Americans who suffer from the disease, nearly half don't succeed in keeping their blood pressure under control, often because they haven't been prescribed the drug that would work best for them. One of the factors causing this problem is that there are “five types of drugs commonly used for treating hypertension, or high blood pressure, a major risk factor for heart attacks and stroke.”

Some of the most common therapies available to treat hypertension include “diuretics, which are cheap, well-tested, and have been around for decades. These drugs boost the release of fluid through the kidneys. Another drug class, beta blockers, slow the heart and thus lower the amount of blood that's pumped. Ace inhibitors, alpha blockers and calcium channel blockers reduce pressure by dilating the blood vessels.”

The difficulty that arises from choosing these drugs is that “doctors often choose among the drugs by trial and error, prescribing several of them in turn to see which works best for a particular patient.” What makes the situation even more problematic for patients and doctors is that “most people need more than one drug to control high blood pressure, making it all the more difficult to ensure a patient is receiving the most effective treatment. In other words, “patients with different physical characteristics respond differently to various hypertension drugs.”

As a result, there is a strong need for more continuing medical education (CME) and custom medicine to address how patients can be given the correct treatment that is best for them. Fortunately, three new studies are now suggesting ways to help make sure patients get the right medications.

As Michael Alderman, a blood-pressure expert at the Albert Einstein College of Medicine in New York City, and a co-author of one of the new studies in hypertension pointed out, the “current prescribing methods are very primitive.” And a consequence of these primitive practices is that “we haven't increased the success rate [in treating hypertension] in 35 years." These comments demand the attention of the medical community to rethink methods and approaches for the diagnosis, prevention and treatment of hypertension.

Making it harder for doctors to find the right treatments for patients is that “little research has focused on matching specific pills to specific patients,” but the new studies, which appear in the latest issue of the American Journal of Hypertension, “represent efforts to provide scientific guidance for doctors treating high blood pressure.” For example:

-   One of the studies shows that some drugs work better in certain ethnic groups than in others.

-   Another study points to the importance of testing patients' levels of renin, a hormone produced by the kidneys, as a guide in prescribing blood-pressure medicine.

Despite the fact that “researchers in each of the studies emphasized that larger-scale trials would be necessary before the findings could become part of official treatment guidelines,” their accomplishments demonstrate a significant breakthrough.

In addition, one of the studies, co-authored by Ajay Gupta of Imperial College London, looked at drug responses among 5,425 patients in various countries and across different ethnic groups. His research confirmed that south Asians, who are often given ace inhibitors as a first-line treatment, respond especially well to this line of treatment.

Dr. Gupta and his colleague’s research also showed that “medical-treatment guidelines, which say that first-line drug therapies should be guided by a patient's age and race,” should also be applied for second-line treatments. For example, “if a calcium channel blocker is first prescribed, a diuretic should be the add-on drug. If a diuretic is first prescribed, a calcium channel blocker should be the second-line treatment.”

The two other studies, which focused on the hormone rennin, discussed how “few doctors today measure a patient's renin level, despite a study in the 1970s that suggested it might be used as a biomarker for prescribing the drugs.” Despite “contradictory evidence that emerged later, which helped keep renin-testing from catching on, one of the new studies, involving 363 patients, confirmed the 1970s finding, showing that measuring the renin level can be an effective method for selecting a blood-pressure medication.”

Specifically, “the research, by a team led by Stephen Turner of the Mayo Clinic in Rochester, Minn., found that a patient with a higher renin level probably should not be treated with a diuretic.” Instead, the authors found that “the patient would probably respond better to a drug, such as a beta blocker, that functions differently in the body.”

This research also concluded that “the predictive effects of renin activity were statistically independent of race, age and other characteristics.” The research also “found that renin levels could also serve as a guide for prescribing add-on therapies for some patients.”

The third study, which involved 945 patients and was led by Dr. Alderman, “found that when an anti-renin drug was used in certain patients with low renin levels, it had the undesirable effect of increasing blood pressure.”

These studies demonstrate that more research and education is needed regarding the treatment of hypertension. In addition, the findings from these studies also “constitute a wake-up call that we should be using renin measurements as a systematic form of help" for prescribing hypertension drugs.

Ultimately, with a condition that affects over 50 million people this should be a main priority for physicians, researchers, and healthcare providers. One way to begin integrating the findings from this study into practice is by working with doctors and CME providers to establish programs that begin to measure and collect data regarding the methods doctors use in choosing hypertension drugs. Through more education about choosing the best methods for prescribing hypertension drugs, CME and custom medicine can begin to address these issues and help make hypertension patients healthier.

Harvard Research Convicted on Fraudulent NIH Primate Research – Immoral Mind

 
Over the past couple of years, the headlines have been heavily dominated by stories focused on money paid to physicians for their noble work with the pharmaceutical industry and medical device makers. While much of the coverage has only focused on the amounts of money spent, instead of the number of lives and money saved by such collaboration, the “conflict of interest” (COI) movement has been urging academic medical centers, professional organizations, journals, and everyone in between to not accept industry funding for everything from research to continuing medical education (CME).

The COI movement has maintained from the very beginning that working with industry creates a conflict of interest because it creates a bias that risks harming patients. Despite the fact the no reliable evidence exists to show any harm to patients, critics of industry funding have asserted that transparency and management of such conflicts are not enough.

A recent development regarding industry funding of research however, sheds some light on the weaknesses of the arguments maintained by the COI movement. Specifically, the case of a researcher at Harvard University demonstrates that the potential for misconduct, bias and unethical behavior is not just a consequence of industry funding.

The case involves the investigation of Marc Hauser, a Harvard University psychology professor who studies primate behavior and animal cognition. Last week, Michael D. Smith, dean of Harvard's Faculty of Arts and Sciences, sent a letter to faculty confirming eight instances of scientific misconduct that Hauser committed.

While the letter did not specify the exact offenses, three papers have received or are receiving modifications. The papers include a 2002 Cognition article (retracted), a 2007 article in Proceedings of the Royal Society B (received an addendum), and a 2007 article in Science.

Consequently, as the Chronicle of Higher Education reported, [T]he investigating committee also found five other studies that either did not result in publications or where the problems were corrected prior to publication. “While different issues were detected for the studies reviewed, overall, the experiments reported were designed and conducted, but there were problems involving data acquisition, data analysis, data retention, and the reporting of research methodologies and results.”

The controversy was also brought to light when a research assistant who worked with Hauser shared emails with the Chronicle of Higher Education, which showed the disagreement with the data. Specifically, Hauser attempted to determine if primates could recognize sound patterns–what some see as a skill for language development. From the Chronicle’s description, the data’s interpretation required determining if a monkey was looking at a stereo speaker as a response to an unusual sound pattern played after a series of similar ones.

In response to these allegations, Hauser acknowledged to the New York Times last week that he had “made some significant mistakes” and that he was “deeply sorry for the problems this case had caused to his students, colleagues and university.”

Ultimately, since federal grants helped fund some of Hauser’s research, as the Dean’s letter describes, federal agencies (PHS Office of Research Integrity, the NSF Office of Inspector General and the U.S. Attorney’s Office for the District of Massachusetts) will continue to investigate. But as the Boston Globe pointed out, Hauser received millions of dollars in federal grants from the government since 2001.

Houser is somewhat famous for his books Wild minds: what animals really think and Moral Minds: How Nature Designed Our Universal Sense of Right and Wrong both books claim some moral equivalency of primates to humans.

It is interesting that major press outlets such as NY Times, Wall Street Journal and Washington Post, all failed to cover this event.

This case demonstrates is that the potential for unethical and biased behavior is found in all sectors of research.  While this case may be an exception, rather than the practice, it still demonstrates the fact that money and influence from different sources besides industry can affect the integrity of scientific conduct. With that said, it would be beneficial if government officials realized that the likelihood of problems with funding is equal across all parties (i.e., industry and government), and that the current trend to attack industry funding is unfair, as this case demonstrates.

While congress and NIH are focused on potiential conflicts of interest working with industry at NIH, some unethical researchers are taking advantage of this missfocus and ccleaning out the store, perhaps spending time on real fraud will prove a better use of our limited resources. 

University of Wisconsin Physician Resigns Over Bureaucracy

 
The war against innovation and collaboration between physicians and industry has claimed another victim—and potentially thousands more in the form of patients—as a “prominent University of Wisconsin cancer researcher resigned last week after university officials began investigating a potential conflict of interest involving his outside business interests.” Fortunately, he is considering other positions that allow him the freedom and independence to work with anyone and everyone he wants.

What is disappointing about this case, which involves “Dr. Minesh Mehta, an internationally recognized expert on human clinical cancer trials,” and winner of the Ladies Home Journal Breakthrough in Innovation Award “comes amid heightened national scrutiny of doctors' ties to industry and the university's own attempts to better monitor such relationships.” In other words, there was no evidence of any harm or wrong doing on the part of Dr. Mehta. Instead, the atmosphere that has been created by media, critics and policymakers has made it almost impossible for researchers to work with industry to advance medicine and their training while still leading a normal career and life.

This case arose back in April, when “the UW-Madison committee responsible for protecting the rights and welfare of participants in research studies became aware of a potential conflict involving Mehta and his paid consulting work with TomoTherapy Inc., a Madison company that makes cancer treatment devices, according to documents obtained by the Wisconsin State Journal.”

The issue that came about surrounds the fact that Dr. Mehta has been the lead researcher of a federally funded clinical trial of a specialized radiation treatment for cancer patients known generically as tomotherapy over the past decade. According to UW-Madison, this created a potential conflict because “the device used to administer the radiation to a majority of participants in the study is made by TomoTherapy.”

Consequently, UW-Madison initiated a formal investigation, and participants in the clinical trial subsequently were told of the potential conflict. In the notification letter to participants, UW-Madison told participants that while it "is not believed that (Mehta's) participation in this research on the use of tomotherapy in any way compromised the results of the study or the safety of the people taking part in the study, we felt that participants in this study should be informed of Dr. Mehta's financial relationship."

Dr. Mehta's ties to TomoTherapy (the company called the same name as the treatment) also became more public last November when “Dr. Eli Glatstein, a University of Pennsylvania School of Medicine professor and a revered figure in oncology research circles, chastised Mehta in an editorial in the International Journal of Radiation Oncology Biology Physics.” Specifically, Dr. Glatstein accused him of not revealing his ties to TomoTherpay when Dr. Mehta criticized a TomoTherapy competitor in the pages of the same scholarly journal. This led Glatstein to group Dr. Mehta into “a generation of people who don't seem to recognize a conflict of interest when it smashes them in the mouth."

Amidst this controversy however, Dr. Mehta firmly maintains that there “is no conflict of interest involving his work.” Rather, he had “been considering leaving UW-Madison since early 2009 and based on the unique and new opportunities that have presented themselves, which is very common in the academic field." After notifying the university of his resignation on May 10, he ended his 22 year career at UW on June 4.

Another reason why this case is so troubling is that even though Dr. Mehta followed all the necessary policies and he “filed reports each year covering his outside business income as required by university policies,” the university still used the “potential” for conflict to investigate his work. Despite the fact that he even “notified the university in 2008 that he was reducing his university appointment by 10 percent to spend time as a consultant for TomoTherapy,” this transparency was not enough.

Adding to this problem is the fact that media articles like this one cover the issue in a way that helps perpetuate criticism against physician-industry collaboration by focusing on his compensation last year, rather than the success TomoTherpay has provided to patients and the outcomes it has shown in clinical care.

Moreover, the fact that Mehta’s professional vitae shows he was chairman of TomoTherapy's medical advisory board from 2001-08, and a video posted on the company's website that describes "his involvement with the development and implementation of TomoTherapy," should be reassuring, not problematic. Patients should want and in fact do want their physicians to have the most experience and training possible, especially when treating serious and life threatening diseases like cancer.  The fact that this therapy is used through a device also constitutes a specific need for physicians like Dr. Mehta who have developed the device and know the designs, techniques, flaws, and best uses to help train other physicians accordingly.

But Dr. Mehta’s involvement with the development and implementation of the device does not create a potential for conflict for two simple reasons. First, the federal research study, which started in 2001, “has never been funded by any corporate support.” Second, the study is designed “to test a general principle — the maximum safe dose of radiation for lung cancer patients — not a particular device.” Those two factors, Dr. Mehta assert, clearly show “there is no direct conflict."

Additionally, as CEO of TomoTherapy Fred Robertson put it, Dr. Mehta is “a man of high integrity who has been very careful to disclose any conflicts of interest.”

Consequently, the fact that the investigation into the potential conflict continues despite Mehta's departure, is misguided. For instance, although Dr. Mehta has been receiving federal funding from NIH since his 2000 grant application, he only began receiving payment as a consultant for TomoTherapy in 2008, and NIH has not expressed any concern thus far of any potential conflicts. In addition, Dr. Mehta was already under three separate management plans, which according to Jim Wells, director of research policy for UW-Madison “generally work.” So if formal investigations are “quite rare,” then how is it that UW-Madison decided to conduct one on a professor who has filed all his annual reports and was following three management plans?

Ultimately, the fact that Dr. Mehta sought “formal and official clearance" from the university prior to initiating his consulting work with TomoTherapy demonstrates the high level integrity he has for working with patients while ensuring transparency. Since the UW-Madison has already expressed to participants that Dr. Mehta’s participation in this research on the use of tomotherapy did not in any way compromise the results of the study or the safety of the people taking part in the study, it is time to put this show to an end.

In the end, UW has already lost one important faculty member, and if we want to continue to attract physicians and researchers to academic medical centers, university policies and administrators would do better by patients and staff by moving away from such strict regulations that hinder innovation and chill physician willingness to participate and collaborate with industry.

Transparency is more than enough for now, at least until someone can show any kind of evidence that demonstrates what harm is done to a patient for a doctor to work with a company to help save patients lives.

Clinical Trial Survey Shows Industry Supported Trials are Successful

 
The Annals of Internal Medicine published an article entitled “Outcome Reporting Among Drug Trials Registered in ClinicalTrials.gov,” which examined whether the funding source of these certain clinical trials was associated with favorable published outcomes.

The observational study of safety and efficacy trials was designed to look at anticholesteremics, antidepressants, antipsychotics, proton-pump inhibitors, and vasodilators conducted between 2000 and 2006. Consequently, among 546 drug trials, 346 (63%) were primarily funded by industry, 74 (14%) by government sources, and 126 (23%) by nonprofit or nonfederal organizations.

According to the study results, trials funded by industry were more likely to be phase 3 or 4 trials (88.7% across groups), to use an active comparator in controlled trials (36.8% across groups), to be multicenter (89.0%), and to enroll more participants (median sample size, 306 participants across groups). Overall, 362 (66.3%) trials had published results.

Consequently, the fact that industry-funded trials reported positive outcomes in 85.4% of publications, compared with 50.0% for government-funded trials and 71.9% for nonprofit or nonfederal organization–funded trials should not be surprising. Later phase trials (Phase III and IV) largely funded by industry have a higher probability of success than early stage trials funded by government and foundations. By trying to associate the more favorable outcomes with success in these phases, which were funded largely by industry, the authors are comparing apples to oranges, and end up writing a paper that oranges have more juice than apples.

The study also found that trials funded by nonprofit or nonfederal sources with industry contributions were also more likely to report positive outcomes than those without industry funding (85.0% vs. 61.2%). Rates of trial publication within 24 months of study completion ranged from 32.4% among industry-funded trials to 56.2% among nonprofit or nonfederal organization–funded trials without industry contributions.

Despite these findings, the study was limited because additional information on study protocols and comprehensive trial results were not available to further explore underlying factors for the association between funding source and outcome reporting.

In fact, one of the researchers, Florence Bourgeois, a faculty member in the division of emergency medicine at Children’s Hospital in Boston, told Newsweek that they didn’t even “know for sure” that industry funding was a factor because it “may be other things that could sway results.” For example, she noted that instead of commercial funding creating bias in trials, it could be “the questions that investigators choose to ask or the type of patient selected or how long the patient population is followed.”

Even though it is clear that other factors have a strong potential to influence clinical trials, Dr. Bourgeois asserted that the study justified the need for more oversight and additional information about the way the trials are designed. She stated that it would be “helpful if study protocols were posted in ClinicalTrials.gov or comprehensive FDA review material of trials reviewed in the drug approval process for every medication made available.”

What is troubling about this study is that it ignores some very simple and obvious facts. First, industry trials are more successful than government. What is that saying about the expertise and level of science being conducted by our own government when our agencies are right half the time and industry is right 85% of the time? 

Second, it is important to realize that the success of industry trials is based on the fact that industry spends money on products and studies on those products when there is a high probability of success. That is how all companies work: invest in something profitable. Investing in health care is no different than any other business, except for the fact that numerous drug and device companies work on orphan drugs and devices for rare diseases, and donate their time, services and products for philanthropic purposes.

Third, the fact that we are seeing more positive results benefits patients because the more beneficial results we see, the more patients will benefit from the drugs that work.  

Fourth, companies are focused on developing and testing drugs as efficiently and effectively as possible to bring products to patients faster. The fact that there may be bias in a study designed by commercial funding to accomplish that purpose should not be shocking because companies don’t have the resources to waste time and money on poorly designed trial, even though the government has unlimited resources and can waste all they want.

Fifth, the job atmosphere and pressure in government versus private industry are exactly the opposite. Where as no one is going to lose their government jobs for poor study design, companies can fail, and jobs can be lost in seconds for trials and products that fail. And finally, one of the reasons why industry trials are so promising is because non profits are less motivated and knowledgeable to conduct studies that are successful.

In the end, if the author was true to his own logic it should follow that if government is having less successful clinical trials, shouldn’t they be the ones needing more oversight?

Everything in society comes with inherent risks and benefits. Just look at all the recalls of toys and cars. Should we believe that companies were biased in creating ways for kids to have fun and adults to get to work to support their families? This study tries to associate biased results with the people who funded them. Does that mean that all of our politicians are biased by the people who contributed campaign donations to them?

Companies survive and exist to make people healthier and live longer. That’s their business, and attacking them for being more successful than government seems childish. Instead of wasting their time figuring out which factors cause trial results to be “biased,” it would probably help if the government determined what industry is doing right to have such success, and what they are doing wrong.