By Meghana Suresh, M.Sc, Medical Writing Team Lead
The Physician Payment Sunshine Act was passed by the US Congress in the year 2010 and the Final Rule was published on February 8, 2013 by Centers for Medicare and Medicaid Services (CMS) as Section 6002 of the Patient Protection and Affordable Care Act (PPACA). The Act requires any applicable manufacturers of drugs, devices, biological, or medical supplies covered by Medicare, Medicaid or the Children’s Health Insurance Program (CHIP) to report ‘certain payments and transfer of value provided to the physicians and hospitals (covered recipients)’ annually, in an electronic format, to the US Department of Health and Human Services (DHHS). In addition, applicable manufacturers and applicable group purchasing organizations (GPOs) are required to report certain physician ownership or investment interests annually.
The mandatory categories to be reported under this Act include: charitable contributions; food and beverages; compensation for services other than consulting; compensation for serving as faculty or as a speaker for an unaccredited and non-certified continuing education program or for an accredited and certified continuing education event; consulting fees; honoraria; gifts; entertainment; travel and lodging; education; royalty or license; current and prospective ownership or investment interests; grants; research; and space rental or facility fees.
The minimum reporting requirements for each payment or transfer of value include: applicable manufacturer name; covered recipient identification information; amount of payment or other transfer of value including the date of payment; name of related covered drug, device, biological or medical supply; form of payment; nature of payment and the name of the entity paid; eligibility for delayed publication; payments to third parties; and contextual information for each payment or other transfer of value.
For research-related payments, applicable manufacturers must report payments that ultimately are paid, in whole or in part, to a covered recipient. For each research-related payment, the applicable manufacturer is required to report the following: name of research institution/other entity or individual receiving payment; total amount; name of study and related covered drug, device, biological or medical supply; principal investigators with detail; context of research; and clinicaltrial.gov identifier. Payments for medical research writing and/or publication would be included in the research payment if the activity was included in the written agreement or research protocol and paid as a part of the research payment.
Applicable manufacturers and applicable GPOs who fail to report are subject to the imposition of civil monetary penalties (CMPs) as per the Section 1128G (b) of the Act. If an applicable manufacturer or applicable GPO fails to submit the required information and if this was unintentional, then the applicable manufacturer or applicable GPO will be subject to a CMP of at least $1,000, but no more than $10,000 for each payment or other transfer of value, or ownership or investment interest not reported as required. The maximum total CMP with respect to each annual submission for failure to report is $150,000. For a known failure to submit required information in a timely manner, an applicable manufacturer or applicable GPO will be subject to a CMP of at least $10,000, but no more than $100,000 for each payment or other transfer of value, or ownership or investment interest not reported as required. The maximum total CMP with respect to each annual submission for a known failure to report is $1,000,000. The factors considered in determining the CMP amount include but are not limited to: the length of time the applicable manufacturer or applicable GPO failed to report; amount of the payment or other transfer of value; level of culpability; nature and amount of information reported in error; and degree of diligence exercised in correcting information reported in error.
Other Key Points About the Sunshine Act:
- The rule requires applicable manufacturers and applicable GPOs to begin data collection by August 1, 2013; submit their first reports by March 31, 2014; and requires CMS to release the data online by September 30, 2014.
- Following the end of the 45-day review and correction period, applicable manufacturers and applicable GPOs will have an additional 15 days to correct data for purposes of resolving disputes, after which they may submit updated data to CMS to finalize their data submission.
- CMS finalized that a CMP may be imposed for failure to report information in a timely, accurate, or complete manner. “This includes failure to report timely or accurately an entire transaction, as well as failure to report timely or accurately certain fields related to a transaction.”
- With respect to preemption, CMS recognized that State and local entities may require reporting of nonrequired categories of information for payments or other transfers of value reported to CMS, which are not required under Federal law.
By Vicki Nelson, Proposal Developer
The term nutraceutical is a word that was coined by Stephen DeFelice, MD in the early 1990’s. Dr. DeFelice is the founder and chairman of the Foundation for Innovation in Medicine in Cranford, NJ. Nutraceutical is a combination of the words “nutrition” and “pharmaceutical” and Dr. DeFelice meant it to describe any substance that is a food or a part of a food and provides medical or health benefits, including the prevention and treatment of disease. Today it is a commonly accepted word in the lay community and is found in the Miriam Webster dictionary. However for the medical community and the FDA the definition is still very unclear.
In the United States the term nutraceutical is primarily used for marketing purposes. Many different types of products can be labeled a nutraceutical such as dietary supplements, vitamins, minerals, botanical, herbs and extracts. The FDA still uses a blanket term of "dietary supplement" for all substances without distinguishing their efficacy, manufacturing process, supporting scientific research, and increased health benefits. All can be marketed without prior FDA approval. There is minimal regulation over what is allowed to be displayed on the label of any product marketed as a nutraceutical and for this reason the medical community is calling for the term to be more clearly identified.
In 1994 the The Dietary Supplement Health and Education Act (DSHEA) made an attempt to identify what a dietary supplement is that did little to clarify the situation. By their definition a dietary supplement is a product taken by mouth that contains a "dietary ingredient" that is intended to supplement the diet. Some would say the biggest accomplishment of the DSHEA Act was that it mandated that the FDA regulate dietary supplements as foods, rather than as drugs. This meant that dietary supplements were not subject to the safety and efficacy testing that is required for pharmaceuticals. The FDA can take action against manufacturers of dietary supplements only after they are proven to be unsafe.
These products can and often do claim to provide health benefits either directly or indirectly in their marketing. Manufacturers usually include a disclaimer on the label that says: “These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease”
The last portion of this disclaimer is precisely what sets a nutraceutical or dietary supplement apart from a pharmaceutical. Pharmaceuticals are intended to diagnose, treat, cure or prevent a disease and companies must prove to the FDA that their product will do exactly what they claim. This requires a heavy investment from pharmaceutical manufacturers in both money and time.
Does this mean that the two are and will always be mutually exclusive? Not necessarily. Estimates predict the global nutraceutical market will reach $250 Billion by 2018 and the largest regional market is the United States and this is certainly getting the attention of the pharmaceutical industry. But, they cannot financially justify spending a decade of more on R&D to not have a product that they can patent.
What we are seeing is an investment by big pharma in nutraceuticals with an emerging market called Medical Foods. Using foods to prevent or treat disease is not a new concept. Ancient cultures have mentioned the use of food for therapeutic reasons for over 5000 years. What we are witnessing is a much refined scientific approach to old concept. Medical foods are formulated to meet certain nutritional requirements for people diagnosed with a specific illness or condition and must be administered under the supervision of a physician. These products are regulated by the FDA and are available only as prescribed by a physician. Although nutraceuticals or supplements may be food based they do not meet these requirements.
In 2011 Nestle SA created a new business unit called Nestle Health Science. Luis Cantarell the President and CEO of Nestle Health Science was quoted as saying this “….this will pioneer a new industry between food and pharma.” Innova Market Insights, 2011 supports this notion in their report by stating that worldwide they have seen more than 100 new medical food product launches since 2009. Although many of these were extensions of existing product lines there are innovative products being introduced. Nestle Health Science acquired a stake in Accera, a company that specializes in medical foods for neurodegenerative disorders such as Alzheimer’s.
Pharmaceutical companies are bringing nutraceuticals into the medical mainstream and they are bringing with it the research, education, marketing, and distribution opportunities that are desperately needed.
By Jeff Harrigan, Research Associate
Employee turnover is costly. There is no industry in which that assertion holds more truth than the biotech industry. In this industry, the average cost of replacing an employee is roughly 50% more than the runner-up aerospace/defense industry.1 The obvious implication here is that turnover, particularly at a biotech company or a clinical research organization (CRO), should be kept to a minimum. Retaining quality employees should be a priority for any company (for many reasons, financial and otherwise), and a key first step in that retention is to hire the right person from the outset. Here are some fundamental elements of recruitment and retention that can help your company acquire the talent it needs, and keep it there:
- College Recruiting: College recruiting can be a very fertile area to explore.1 5 Maintaining a presence at campus recruiting events will not only facilitate access to bright young candidates, but help to generate interest in the pharma/biotech industry. Some human resource experts even advocate sending representation to high school events to begin developing the industry’s next generation.5 College recruitment can provide great opportunities to “get in on the ground floor” of the development of talented young prospects who can become invaluable resources. See how MMS builds a campus presence in a previous MMS blog post by Senior Biostatistician Justin Sjogren.
- Employer Branding: The idea of employer branding is to build a reputation as a good place to work. You want people to wish they could work there. For a CRO, this doesn’t mean building a national image akin to those of ESPN or Google. It is more important, then, for a CRO to cultivate a stellar reputation within the industry. To be recognized among peers (and potential future employees) as a first-rate employer can go a long way toward drawing in top talent.2 4 5 6 As part of the MMS internal brand we focus on colleague development with a program entitled MCEP (MMS Colleague Exchange Program). This program allows colleagues from our Asia headquarters to visit our US headquarters and vice versa. During the time spent at different locations colleagues train, receive training, and work side-by-side with other employees. They then take this information back to their home office to discuss with the rest of their teams. It allows for a greater feeling of togetherness and collaboration between offices.
- Organizational Culture: A company’s organizational culture is absolutely paramount in keeping employees happy. An organization’s culture encompasses a multitude of factors that may affect an employee’s satisfaction. Some of the primary factors are opportunity for professional growth and upward mobility, job security, compensation, recognition and appreciation, and, perhaps most importantly, relationships with co-workers and managers.1 2 4 5 6 Good relationships with co-workers and managers have been cited as the number one and number two reasons that employees remain with an organization; compensation and benefits are down at number four andnumber five on that list.1 The third biggest reason employees leave a job, meanwhile, is a lack of recognition or appreciation.1 One way to address this concern was observed, of all places, at a Harley-Davidson rally.3 Award-winning presenter and lecturer Mark Scharenbroich repeatedly witnessed a common interaction among bikers, whereby two strangers could make a meaningful connection with the simple words, “Nice bike.” This phrase, whose significance is far greater than the sum of its parts, fostered a feeling of community, of belonging. That feeling of belonging and recognition is something that employees truly value in the workplace.1 6 The “nice bike” analogy simply illustrates how easy it can be to promote this kind of work environment. Learn more about the cultural qualities of the highly effective teams here at MMS in an article by Kelly J. Hill, Director of Project & Account Management.
- Recruiting Agency: Hiring a recruiting agency is not so much a necessity, but it is very much a worthy consideration. When talking about recruitment and retention, the conversation seems to inevitably turn to the option of outsourcing to an agency, and it can be a debatable topic of discussion. A recruiting agency might contend that a client company would benefit from leveraging the agency’s global networks to locate the right candidates while freeing up the client’s staff to focus on other business. 5 Some HR experts, however, warn that an agency or agent can be an expensive but unreliable resource with the potential to produce inadequate candidates. 6 Hearing both sides of this conversation, it seems prudent, then, to approach recruiting agencies with a degree of circumspection. Outsourcing recruitment has its risks, but there are quality recruiters and agencies out there with years of industry-specific experience and a reputation within the industry that can track down quality candidates.
These are not revolutionary new tactics. These are simple conventions that have produced success in the past and stand as pillars of recruitment and retention. This certainly is not a comprehensive list, either. What are some other strategies your company uses to reel in and hang onto valued employees?
By Dr. N. Arulmozhi, MPT, PGDCR & PV, Drug Safety Associate
The development of new and effective medicinal products makes a positive contribution to the health and well-being of individuals. However, there is a need to improve pharmacovigilance (PV) systems to more effectively monitor and take action on safety issues associated with medicines to enhance their contribution to public health. This article looks at the current trends driving the development of PV strategies in order to achieve this aim.
Factors behind the development of current trends
- Globalization of the pharmaceutical market.
- Development of innovative products.
- Increasing public awareness and changing expectation with regards to the safety of medicines.
- Large costs associated with drug safety.
In the past, PV has concentrated primarily on post-marketing safety surveillance. In recent years, it has been shifted towards systematic PV throughout the product life cycle (preclinical studies to post marketing surveillance) as recommended by the CIOMS V Working Group. The effective PV system needs to integrate input from all stakeholders, both within an organization and externally.
Effective integrated PV also includes preclinical and clinical operations, clinical data management, statistics, medical writing, regulatory authorities/activities, IT and medical information, sales and marketing, and public relations.
The main method currently used to gather information on a drug in the pre-marketing phase is by conducting clinical trials.
Data Mining Technology in Spontaneous Reporting System
- In the past, signal detection in spontaneous reporting has mainly occurred on the basis of case-by-case analyses of reports. Recently, the reports are validated by ‘data mining’.
- The term ‘data mining’ refers to the principle of analyzing data from different perspectives and extracting the relevant information.
- Algorithms are often used to determine hidden patterns of associations or unexpected occurrences, i.e. signals in large databases.
Three Current Approaches in Data Mining Methods
- Proportional Reporting Ratios (PPRs): This method compares the proportion of reports for a specific Adverse Drug Reaction (ADR) reported for a drug with the proportion for that ADR in all other drugs. The calculation is analogous to that of relative risk. Using the same information, it is also possible to calculate a ‘reporting odds ratio’.
- Bayesian Confidence Propagation Neural Network (BCPNN): This approach uses Bayesian statistics to analyze all reported ADR combinations. Strong relationships in the data are highlighted relative to general reporting of suspected adverse effects. The WHO Collaborating Centre for International Drug Monitoring uses this method for data mining.
- Multi-Item Gamma Poisson Shrinker (MGPS): It is used by the FDA for data mining of their spontaneous report’s database. The MGPS algorithm computes signal scores for pairs, and for higher-order (e.g. triplet, quadruplet). The significant more frequent combinations of drugs and events would predict.
- Innovation in drug safety monitoring needs ensure that emerging problems are promptly recognized and dealt with, and that information and solutions are effectively communicated.
- “Process oriented evidence” is essential to protect public health.
- The creation of purposeful, coordinated, worldwide support amongst politicians, officials, scientists and clinicians will demonstrate benefits of PV to public health and patient safety.
- In order to further prove PV as a science, it is essential that academia develops new methods which can strengthen the current system.
- Furthermore, when facing an ADR, questions that patients as well as the treating physician can ask are: will this ADR disappear?; How long will it take before it does?; What treatment is needed?
- The pharmacogenetics could play a role in identifying individual risk factors for the occurrence of certain ADRs.
- In the future, PV has to concentrate on the patients as a source of information in addition to the more traditional groups, such as the health professionals.
- Transparency and communication would strengthen consumer reporting, which is a positive step towards involving consumers more in PV.
The PV of tomorrow must be able to identify new safety issues without delay. Furthermore, PV methods must also be able to describe which patients are at risk of developing an ADR and what the course of the ADR is. If we succeed herein, patient’s confidence in drugs will return.
- World Health Organisation Collaborating Centre for International Drug monitoring (2007), The importance of pharmacovigilance. Available at http://www.who-umc.org.
- European Medicines Agency (EMEA) (2006) Assessment of the European Community system of pharmacovigilance. Available at http://www.cbg-meb.nl/NL/docs/nieuws/rapp-fraunhofer.pdf.
- European Medicines Agency (EMEA) (2007) European risk management strategy: achievements to date. Available at http:// www.emea.europa.eu/pdfs/human/phv/30816707en.pdf. Cited 18 Dec 2007.
- Strom BL, (Ed) (2005). Pharmacoepidemiology, 4th edition. Wiley, Chichester.
- Pharmacovigilance: methods, recent developments and future perspectives. L.Harmark, A.C. Van Groothest. Eur J Clin Pharmacol (2008) 64:743–752. https://www.lim.lareb.nl/getmedia/afa6e9f7-6362-455c-86fc-1cd10fb7b6f9/EJCP-2008-64-743-752-Pharmacovigilance-methods,-recent-developments-and-future-perspectives.pdf.
By Krithi Rao Bindal, Ph.D., Medical Writer
The Newsweek headline on May 27, 2001 announced “A Cure for Cancer?”
Just weeks before this headline, the United States Food and Drug Administration (FDA) announced the accelerated approval of a new powerful anti-cancer drug after a review period of only two and a half months, making it the fastest FDA-approved cancer drug in history. Scientists and physicians were thrilled that one of the first targeted tyrosine kinase inhibitors, Gleevec, demonstrated efficacy in patients with chronic myelogenous leukemia (CML) and received accelerated approval in record‑breaking time. Less than two years later, accelerated approval of Gleevec was converted to regular approval for the treatment of CML patients in blast crisis, accelerated phase, or chronic phase after interferon therapy. According to one of the key scientists involved in the Gleevec story, Dr. Owen Witte stated that, “to see the fruits of your basic science evolve [in one scientific lifetime] and end up in a therapeutic that actually makes a major difference in people’s lives is an extremely rewarding feeling.” While Gleevec is hardly a cure for cancer, the drug has clearly made history as a medical, scientific and regulatory breakthrough. This success story is an example of FDAs accelerated approval procedures and highlights the impact of this regulatory pathway.
In 1992, the FDA implemented new accelerated approval regulations for expediting the regulatory process for drugs designed to treat life-threatening diseases where adequate treatments are not available. Under the guidelines for accelerated approval regulations subpart H, approval is based on a surrogate endpoint that is likely to predict clinical benefit or on evidence of an effect on a clinical endpoint other than survival or irreversible morbidity [21 CFR 314.510]. A surrogate endpoint can be a marker, a laboratory measurement, or physical sign that represents a clinically-meaningful outcome.
Following the addition of Subpart H to new drug application regulations, President Clinton’s office released a document entitled Reinventing the Regulation of Cancer Drugs, which described the application of the accelerated approval regulations by the FDA to new cancer treatments. Under these specifications, accelerated approval of oncologic drugs may be based on the demonstration of tumor size reduction in patients with refractory disease or in patients whose disease had no effective therapy. For example, the FDA can approve a drug based on the evidence that treatment results in tumor shrinkage rather than whether it extends the survival of cancer patients, a study that may take a considerably longer amount of time. The pharmaceutical company is still required to conduct post‑marketing phase IV confirmatory trials to confirm that tumor shrinkage actually correlates with survival. If a clinical benefit is demonstrated in phase IV trials, the FDA can grant regular approval for the drug. If no potential clinical benefit is observed, the FDA has regulations to remove the drug from the market. From 1992 to 2010, 35 oncological drugs or biologics have gained accelerated approval. Of these, 20 drug products have received regular approval for one or more indication. During the Annual Meeting of the American Society of Clinical Oncology 2003, Hirschfeld et. al. presented data demonstrating that the median time from investigational new drug filing to marketing approval was 2,000 days (5.5 years) shorter for drugs approved by the accelerated approval pathway. Therefore, these regulations have undeniably served the purpose of getting promising new agents to the bedside in as little time as possible.
Despite the impact of FDA’s accelerated approval regulations, the process has increasingly been criticized. The risk associated with bringing a drug to market solely on the basis of surrogate endpoints that may not have any real clinical benefit has been noted. For example, a biomarker such as prostate specific antigen (PSA) may be a correlate and not necessarily a surrogate of a clinical-efficacy measure. When considering response rate (RR) as a surrogate endpoint, is there a minimum RR that is predictive of clinical benefit? Dually notable is the issue of speed versus safety. Since accelerated approval is generally based on Phase II studies with a small number of patients, is there sufficient data to ensure drug safety? These are just some of the issues that are currently being considered by the FDA and pharmaceutical companies, keeping in mind what is in the best interest of the cancer patient.
Regulation in oncology is a continually evolving process. However, the implementation of accelerated approval regulations has certainly made an impact on the development and availability of cancer drugs, such as the case with the “miracle drug” Gleevec.
“Applications for FDA Approval to Market a New Drug.” Code of Federal Regulations Title 21 Part 314. Washington, DC: U.S. Government Printing Office; 2011 ed.
Clinton W, Gore A. Reinventing the regulation of cancer drugs. National performance review. March 1996.
Dagher R, Johnson J, Williams G, Keegan P, Pazdur R. Accelerated approval of oncology products: A decade of experience. Journal of the National Cancer Institute 2004; 96:1500-1509.
Ellenberg S. Accelerated approval of oncology drugs: Can we do better? Journal of the National Cancer Institute 2011; 103:1-2.
Fleming TR. Surrogate endpoints and FDA’s accelerated approval process. Health Affairs 2005; 24:67-78.
New England Healthcare Institute. Targeting Cancer: Innovation in the treatment of chronic myelogenous leukemia. New England Healthcare Institute Innovation Series 2004.
Richard L. Schilsky. Hurry Up and Wait: Is Accelerated Approval of New Cancer Drugs in the Best Interests of Cancer Patients? Journal of Clinical Oncology 2003; 21(20): 3718-3720.
By Joe Archer, Associate Director, Data Sciences & Disclosure Services
Federal mandates calling for transparency of clinical trial information have been in place in the United States since 1997, but a recent move will finally give the current FDA (Food and Drug Administration) law some teeth to enforce compliance. In September, the US Department of Health & Human Services (HHS) transferred authority from HHS control to the FDA to oversee information that is filed to ClinicalsTrials.gov (“clinical trial registry data bank”), and seek out those who fail to file, or file misleading or false data, according to a statement in the Federal Register.(1)
Why is this transfer of responsibility important? As we travel over the last 15 years and look at deficiencies in the laws governing disclosure, assessing how these deficiencies may have contributed to the existing lack of compliance in disclosure reporting, it is easy to conclude that laws are only as good as the people who enforce them. Important to also note that historically the FDA has been an enforcement agency (2), whereas the HHS/NIH is not.
The Food and Drug Administration Modernization Act (FDAMA) of 1997, Section 113, is responsible for establishing the ClinicalTrials.gov databank. It was the first US trial disclosure law designed to provide the public with information about ongoing and completed clinical trials, specifically for serious or life-threatening diseases or conditions where available treatment options were limited. However, with no penalties or enforcement built into the law, compliance was low. A FDA analysis discovered in 2002 that only 48% of trials of cancer drugs were being registered and trials for other serious diseases registered less than 10% of the time. (3) Aside from these small targeted analyses being conducted and showing low percentages for compliance, another problem existed in that agencies had no overall mechanism in place for tracking compliance and identifying studies that should have been registered, but were not.
In 2007, the Food and Drug Administration Amendment (FDAAA) Act, Section 801, expanded the clinical trial reporting requirements to include the registration of most interventional studies (not just limited to serious or life-threatening diseases or conditions) and added the posting of results for applicable clinical trials.
This new law had a mechanism for tracking compliance through a form submitted with every FDA application/submission that certifies compliance was being met under Public Law, including a list of each applicable study through an assigned NCT Number(s) on the form. It also has penalties described (e.g., up to $10,000/day) for non-compliance along with enforcement being defined as the following two-step process:
- Notice to Director of NIH: FDA notifies the NIH about change in status of a drug applications (e.g., approval, non-approval, withdrawal) for studies accompanied by a certification
- Notice of Compliance: NIH notifies sponsors if their information in the databank is non-compliant under FDAAA; requesting a remedy within 30 days of notification.
However, as of 4Q2009 (two years after the law went into effect) there was still no system in place for the FDA to notify NIH and no enforcement plan yet established. (4) It should be noted though that this law does include steps for additional rulemaking to take place that will help workout many of these issues, and in the meantime, FDA has communicated that they expect “good faith compliance” with the statutory requirements and expect that researchers will put internal procedures in place to ensure compliance. (4) Let’s look at how trial sponsors continued to comply with law following 4Q2009:
- In August 2010, the NIH sent notices to the responsible parties of approximately 21,000 (9,000 industry and 12,000 non-industry) trials that appeared to be missing data or lacking results in ClinicalTrials.gov. This act resulted in the NIH only receiving responses and/or the data corrections for about 30% of these studies. And even though the pharmaceutical and medical device industries seem to get the most negative publicity from the media when it comes to transparency of trial information, the NIH had found that academic institutions were compliant with FDAAA results postings less than 5% of the time. (5)
- In February 2012, three House lawmakers (Reps. Henry Waxman(D-CA), Ed Markey (D-MA), and Diana DeGette (D-CO)) issued letters to FDA Commissioner Dr. Margaret Hamburg and NIH Director Francis Collins expressing their concern over a report published in the British Medical Journal (“BMJ”) documenting the underreporting of results of clinical studies on ClinicalTrials.gov. A database search of trials registered on ClinicalTrials.gov showed that of the 738 trials that were classified as subject to mandatory reporting, only 22% had reported results.(6) FDA and NIH both disputed some aspects of the study, but as Andrew Prayle an author of the BMJ paper followed up saying, “it is not surprising that they reached different conclusions (than the study), but can they account for all of the 78% of trials which were not reported?”(7)
As seen above, compliance continues to struggle. Even with laws that establish mechanisms for tracking compliance along with the defining of penalties, it is still important that laws are enforced.
The FDA has stated that it can enforce FDAAA from the statute when warranted. But this has only been apparent when other compliance issues are the driving force, such as a string of corporate integrity agreements (CIAs) with the U.S. Office of the Inspector General (OIG) in which clinical trial data disclosure requirements were included along with other compliance issues.(8)
So what message can be sent with this delegation of authority? Current law says that if there is a finding of noncompliance, the sponsor or investigator of an applicable clinical trial has 30 days to reconcile. If there is still noncompliance after 30 days, FDAAA added language for penalties up to $10,000 for each day out of compliance. In these dismal economic times there is doubt that the federal government has the funding necessary for adding resources to conduct this oversight; however, fining one of the wealthiest industries in the world could more than cover this shortfall (and possibly fund a few other government programs)? Is this delegation of authority setting up the framework for bringing in new government revenue while at the same time addressing a chronic problem and boosting transparency in clinical research?
- Federal Register
- HHS Delegates FDA Authority to Enforce ClinicalTrials.gov Reporting Requirements
- Clinical Trials Reporting and Publication, Congressional Research Service for Congress
- FDAAA Title VIII (PL 110-85, Section 801) Expanded Clinical Trials Registry and Results Database – An FDA Update; Drug Information Association (3rd Annual Clinical Trials Disclosure Workshop), October 7, 2009.
- ClinicalTrials.gov Registration and Results Reporting: Updates and Recent Activity. Journal of Clinical Research Best Practices. Vol 7, No. 2, February 2011.
- BMJ Article on Clinical Trial Reporting Foments Discontent on Capital Hill
- FDA says study overestimated non-compliance with data-reporting laws
- Clinical Trial Data Disclosure: The Pace Quickens, Journal of Clinical Research Best Practices, Vol 8, No 10, October 2012
By Lisa Pierchala, MPH, Principal Medical Writer
Whether it’s the completion of a clinical study report (CSR) for a clinical trial, or the completion of a submission document for a drug development program, medical writing represents the culmination of many people’s work over the course of many years. Due to the number of stakeholders involved across multiple functional areas, medical writing tends to be a consensus‑driven process, representing many contributor’s thoughts and ideas. Building the right review team can significantly contribute to successfully completing documents in a timely and efficient manner. So while there’s no “best” structure for a document review team, keeping in mind some simple suggestions can help to ensure that the document review team works effectively together and with the medical writer to produce a high quality end product.
- Less is more. While everyone loves being able to put their 2 cents in, sometimes smaller a review team allows for more flexible, efficient document review. Having a large review team increases the number of reviewers, comments, and ultimately, time spent vetting comments and incorporating changes. Limiting document review to key individuals can create a robust, yet effective review team.
- Representation of 1 individual from each functional line. While there are many individuals who contribute to the completion of a clinical trial or a regulatory submission, often, 1 key member from each functional line can provide all the input needed for writing of the document. If multiple individuals are included from 1 functional line (for example, 2 statisticians), they should function as 1 group, including internally discussing any suggested revisions to the document, coming to a consensus on required changes, and providing 1 set of collated comments to the medical writer.
- Identify any external team members. Determining if any external key opinion leaders (KOLs) or consultants will be reviewing the documents should ideally be done as early in the document drafting/review process as possible. Often there may be limitations related to system access or sharing of confidential information with the KOL that can take time to set up and resolve. Maximizing a KOL’s expertise can enhance the quality of the final document.
- How and when will Senior Management be involved? If providing a comprehensive review of the document or high-level, strategic input, senior management should be involved as early as possible in the document review process. This will ensure that the project team is aligned with senior management at the outset of document development, rather than at the end, which can often lead to substantial revisions when time is limited.
- Considerations for conflicting workloads. It certainly sometimes feels like everyone has too much on their plate at once; however, real consideration should be given for including a reviewer who has multiple conflicting projects that may limit his/her ability to review the document in a timely manner, and in as much detail as necessary. Naming back-up reviewers at the outset of document development can allow for flexible review in the event that a team member is unable to meet deadlines, and can keep the overall document timelines on track.
Effective document review teams can significantly increase the quality of an overall document as well as decrease the time and effort expended to complete it. The right team members can ensure that the final product represents the most comprehensive and accurate account of what happened during the course of a clinical trial or a drug development program, and can work together with the medical writer to make the process as efficient as possible.
By Joe Archer, Associate Director, Data Sciences & Disclosure Services
A group of House Democrats led by Congressman Edward Markey (D-Mass.) on Aug. 2 introduced the Trial and Experimental Studies Transparency (TEST) Act of 2012 (H.R. 6272), legislation that "updates and expands the clinical trial registry data bank—ClinicalTrials.gov—with stronger reporting requirements," according to a press release dated that same day1.
This proposed legislation is yet another step to address the increasing demand for greater transparency of clinical trial information. As we have seen in the past, the impetus for change in disclosure legislation can usually be traced back to a demand from the public and not-for-profit organizations; here is an abbreviated timeline highlighting this trend:
The TEST Act is meant to close clinical trial loopholes created by legislation and initiatives from the past 30-years and bring certainty and transparency to life-saving research studies. One of these loopholes results in registered trials never reporting study results (e.g., including safety data), putting future human participants at risk if a different company decides to develop the same or similar drug. TEST would achieve a fuller accountability of clinical trial information by expanding requirements to include the following:
- Require all interventional (including phase 1) biomedical studies on humans to be registered with the database before the participant is enrolled in the trial
- Key impact:
- Addition of phase 1 studies which are currently not posted (Note: Sponsors conduct an average of five Phase 1 studies per drug, depending on the type of product, orphan designation, and review status2).
- Postings of inform consent forms and full protocol documents, including all dated amendments to the initial version of such documents, as approved by IRB/committees
- Key impact:
- Risk associated with exposing proprietary information contained within documents
- Additional operational support to facilitate the document management
- Strengthen reporting requirements so that results from all covered trials (including both investigational and marketed drugs and devices) are posted on the database within one year of the completion of the trial; delays are allowed for an additional year for interventions that have never before been approved for any use
- Key impact: Reporting results of investigational products is a significant expansion of existing requirements of only reporting marketed drug/devices
- Instruct the Secretary of HHS to undergo a rulemaking to require foreign trials that are used to support an application for marketing in the U.S. to comply with disclosure requirements
- Key impact: This is a significant addition since 80% of the drugs entering the US market in 2008 were clinically tested overseas
- Ensure enforcement of law by instructing NIH and the FDA to provide a report to Congress regarding the implementation and compliance with the database requirements
- Key impact: Non-compliance can get costly with up to $10,000/day penalties3
According to an article published in the January 2012 issue of the BMJ (“Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study”), a review of trials registered on ClinicalTrials.gov in 2009 and covered by the 2007 FDA Amendments Act (“FDAAA”) showed that of the 738 trials classified as subject to mandatory reporting, only 163 (22%) had reported results. Through the new regulations proposed in the TEST Act, and the enforcement to follow, compliance and the quality, timing and completeness of clinical disclosure information will surely be tested. And the increased demand for transparency is not just limited to the US, with 18 mandatory country registries existing worldwide and a growing number with pending legislation.
Q. How can sponsors of clinical trials ensure compliance (e.g., mitigating risk) with current posting requirements, while managing the increase demand for transparency in both the US and worldwide?
A. As the demand for transparency has increased incrementally throughout the years, it is critical that operations in the following areas are put in place to offset the increase in risk:
- People: Need a mix of project managers to facilitate workflow and medical writers to author summaries.
- Processes: Ensure an integrated workflow that can encompass tracking, assessments, document management, summarization, review & approval, quality control, data transfer, query exchange, site/status updates…and re-use of information for international reporting. We recommend a centralized team to manage workflow and oversee all process, systems, quality and compliance.
- System: Can serve as a centralized and definitive (“single source”) catalogue of your summary information, with functionality to facilitate all workflow.
By Regina Parott, Associate Manager, Medical Writing
Clinical study reports (CSRs) describe the methods and results for each individual clinical trial. CSRs are included in the clinical part of the submission, so it’s important they are well written and easy to understand. As almost every clinical trial protocol is unique, the CSRs that describe their results will also need to be uniquely crafted. There are ICH guidelines (ICH E3) about what to do in the CSR but here are a couple of informal tips about what NOT to do when writing a CSR:
- Ignore the study objectives. The results of the CSR should be presented in a way that allows the reader to easily determine the outcome of the study objectives. Some studies may be very complex with multiple groups, endpoints, and types of analyses. It is important to pay attention to the study objectives to help organize the results and guide the reader. If a study objective was to compare an endpoint by demographic, it’s important that the results and conclusions highlight this comparison. Don’t include 1 demographic endpoint in 1 paragraph and another demographic in another paragraph and neglect to make comparison between the groups. Instead, guide the reader as to how the comparison should be interpreted.
- Use inconsistent terminology. Using inconsistent terminology will confuse the reader and make it difficult to follow the document, which may distract away from the message of the CSR. Readers may be left to wonder whether the different terms are describing the same thing. To avoid confusion, the CSR should be carefully written and reviewed for consistent terminology throughout the document.
- Focus on post-hoc analyses. While it’s acceptable to present post-hoc analyses, this should be done minimally and should be described as such in the CSR. For example, if the statistical analyses were planned on 1 population, then those are the results that should be presented primarily in the results and conclusion section and also in the synopsis. Even if the study team decides after the fact that analyses on another population provides a more accurate view of the analysis, the emphasis should still be on the planned population.
- Minimize negative results. Negative results, such as safety issues or lack of efficacy, should never be hidden or minimized. If an unexpected safety trend occurred, it’s important that it is thoroughly described in the CSR by providing the supportive details and ensuring this information is carried through to the discussion. When negative results are minimized, it looks as though something is being hidden or ignored, in which case the reviewer is left wondering why this occurred and it may look worse than it actually is.
- Forget the big picture. It’s important not to forget the big picture of the drug program. Individual clinical trials do not occur in a vacuum. Think about questions such as ‘what is the target population of the compound’ or ‘what is the expected safety profile of the compound’. For example, if the target population for a compound is an elderly population, consider devoting more text to adverse events that may be especially concerning to an elderly population.
By Lisa Pierchala, MPH, Principle Medical Writer
A medical writer often has to be a jack of all trades in order to ensure accurate, on-time completion of clinical documents. Document review provides a critical opportunity for the medical writer to elicit value-added review from team members. The medical writer can lead strategically by clarifying team members’ roles and responsibilities, setting clear expectations for reviewers, and setting “ground rules” for document reviewers at the outset of the project. The below are suggestions for medical writers to bring effective solutions to document review and ensure that the process goes as smoothly and efficiently as possible.
- Define individuals as the ‘Document Owner’ and the ‘Content Owner’ and what responsibilities are assigned to each. The ‘Document Owner’ would typically be the medical writer, and is the individual who is accountable for the physical integrity of the document, making certain that all comments from reviewers have been correctly incorporated, and ensuring that everything is completed within the given timeline. The ‘Content Owner’ may typically be a clinician, and is the individual who is responsible for ensuring that the scientific content is accurate and that the presentation/interpretation of data is aligned with key messages and objectives. Determining who these individuals will be prior to writing the document can help reduce confusion about roles during document review when time is usually more limited.
- Clarify the hierarchy of reviewers. In the event of conflicting comments, it is important to know whose comments should take precedence and who the ultimate decision-maker will be. If a ‘Content Owner’ has been assigned to the document, that individual can also fulfill the role of primary decision-maker in regards to conflicting comments.
- Define which section(s) each reviewer is responsible for and where he/she should focus his/her review. A critical opportunity for the medical writer to improve the quality of comments received during document review is to define which sections of the document each reviewer is responsible for. For most documents, every reviewer does not necessarily need to review every section of a document. Utilizing the talent and expertise of team members by focusing on specific sections ensures a comprehensive and robust review.
- Require multiple reviewers from 1 functional line to provide 1 set of collated comments. If there are multiple reviewers on the team from 1 functional line (for example, 2 statisticians), requiring 1 set of collated comments will encourage reviewers to internally discuss their comments prior to sending them to the medical writer. This will ultimately minimize the medical writer’s time during comment resolution and incorporation.
- Identify who will be providing comments versus who will be included on the review as a courtesy FYI. Often, there can be many more people included on the distribution of a document for review than will actually be providing comments. Identifying those who are required to provide comments will help the medical writer focus on who he/she needs to get input from rather than following up with many more individuals than needed. A simple suggestion is to include those required to provide comments in the ‘To’ line of an email and to include those receiving a courtesy FYI in the ‘CC’ line.
- Define the use of drop-in text. If a contributor will be providing a specific section to be dropped into the document, it is important for the medical writer to understand when this content will be received. It is also important for the medical writer to discuss with the contributor whether or not changes can be made to the text to improve clarity, or if the contributor expects the text to be included exactly as provided. This ensures that the expectations for the writer are clear when drop-in text is received.
Taking the initiative as a medical writer to set expectations of reviewers can enhance the overall process of clinical document review. The successfully employed strategies above can help to minimize time and maximize efficiency for your document review teams.