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 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.
By Pratima Bhat B.E (BT), Medical Writer
First let’s see what patent ever-greening is and how it came into existence?
Patent ever-greening refers to a strategy of obtaining multiple patents that covers various aspects of the same product. Even though it is not a formal concept of patent law, patent owners utilize this process to extend their monopoly privileges.
Some examples include seeking subsequent patents on derivatives of existing drugs, altering the mixture of isomers, identifying compounds with the same molecular formula but different structural formulas, or patenting methods of administration of an existing drug.
It has been in practice since the passage of the Waxman-Hatch legislation (Drug price competition and Patent term restoration act) in 1984, in which the pioneer drug can receive an extension term equal to one-half the time of the investigational new drug (IND) period, running from the start of the human clinical trial to the time till the new drug application (NDA) is submitted.
Evergreening strategies usually followed by the pharmaceutical industries involve:
- Redundant extensions and creations of ‘next generation drugs’ which result in superfluous variation to a product and then patenting it as a new application.
- Prescription to over-the-counter (OTC) switch.
- Exclusive partnerships with cream of generic drug players in the market prior to drug patent expiry thus significantly enhancing the brand value and interim earning royalties on the product.
- Defensive pricing strategies practice wherein the innovator companies decrease the price of the product in line with the generic players for healthy competition and
- Establishment of subsidiary units by respective innovator companies in generic domain before the advent of rival generic players.
How does it affect?
Extending the patent period seizes the generic drug manufacturing. Once the generic drugs are being produced, the price of the drug can drop by as much as 90%. Additional costs caused by delay in generic entry can be very significant for the public health budgets and ultimately the consumer.
The European Commission estimated a loss of around three billion Euros due to delays in the entry of generic products caused by misuse of the patent system (European Commission, 2009). In 2002, an extensive and lengthy inquiry by the US Federal Trade Commission (FTC), found that the Waxman-Hatch legislation had resulted in as many as 75% of new drug applications by the generic drug manufacturers experiencing legal actions under patent laws by the original brand name patent owner.
This process helps in extending the exclusivity of the manufacturer over the drug however this process has left a wider gap between innovation and access. Competition leads to innovation, prolonging the protection of ideas may freeze the development and utility of the product.
Can it be controlled?
Even though the courts have made some minimal efforts to limit evergreening practices using existing doctrines, it fails to completely abolish this practice from the industry. In 2005, India took a proactive step and amended the Indian Patent Act to introduce, inter alia, to curb evergreening practices by statutorily prohibiting these practices.
Section 3(d) of India’s Patent Act states that the following are not inventions:
“The mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process results in a new product or employs at least one reactant. Explanation - For the purpose of this clause, salts, esters, polymorphs, metabolites, pure form, particle size, isomers, and mixture of isomers, complexes, combinations and other derivatives of known substances shall be considered to be same substance, unless they differ significantly in properties with regard to efficacy.”
Australian law also includes safeguards against evergreening, by introducing penalties for such activities in Section 26C and 26D of Australia Patent Act 1990 and a mechanism for damages to be paid to the government for proven evergreening practices.
Article 18.9.4 of the Republic of Korea-United States Free Trade Agreement (KORUSFTA) has been specifically drafted to permit the establishment of pharmaceutical patent “anti-evergreening” oversight agency.
To Conclude: The patent evergreening promotes development of unfair means of competition. Enhanced intellectual property scrutiny may remove the roadblock for generic drugs and thereby provide the masses with cost effective medicines. This will be required to bring balance between inventions and affordability. If we see the actions taken by a few countries, it leaves others with a ray of hope.
Will the patent rights be utilized in a proper way for the benefit of all or will only a minor part of population get benefits out of it?
By Malarkodi S. Moorthy, M.Sc., M.Phil., Medical Writer
In 2010, the International Conference on Harmonization (ICH) rolled out its E2F Development Safety Update Report (DSUR) guideline. The DSUR is similar to the US’s Investigational New Drug Annual Report (IND-AR) and the EU’s Annual Safety Report (ASR) in that its purpose is to provide a brief overview of safety for a project on an annual basis.
Although both the Food & Drug Administration (FDA) and EU Clinical Trial Directive required what is termed as IND AR and ASR, respectively, the content, format and timings differed between the US and EU reports. Considering that most contemporary trials are multinational, a need was felt towards harmonizing these requirements and to provide a uniform standard acceptable to all regulatory agencies across the world. The concept of a DSUR was first introduced by the CIOMS VI working group and taken forward by the CIOMS VII working group. In 2008, the ICH published a draft guideline E2F on DSUR, which has been updated in August, 2010, incorporating background, objective and scope of DSUR and providing guidance on DSUR contents.
This report is now expected annually by the EMA (implemented from September 1, 2011) and is accepted annually by the FDA (released in August 2011 although the FDA still accepts IND-ARs). There are numerous similarities among the DSUR, IND-AR, and ASR since they share a common purpose. However, some of the ways in which they achieve that purpose differ in the details. Major features of the DSUR are that it covers an entire Investigational Medicinal Product (IMP) rather than just an indication, and that much of its information is cumulative from inception of the project.
FDA’s planned updates for Module 1
Among these is a new Section 1.13.15, for the DSUR, but FDA’s Module 1 update is not expected to be implemented until early 2013.
As per Connie Robinson (FDA personnel), “Currently for an IND, it would be acceptable to place the DSUR as a single document in Section 1.13.3 Summary of Safety Information. You should state that the DSUR is being submitted in place of the IND annual report in the cover letter and provide a link to the document if possible. If information (other than the granular annual report information) is expected as a part of the DSUR, but the information should be placed in its own designated eCTD location.”
More information about the DSUR would be forthcoming along with the implementation of the updates to Module 1.
Usefulness of DSUR
DSURs, which are an enhanced report over the previous required reports, contain not only an evaluation of safety information collected in the past year but also includes a cumulative review of existing safety information. This evaluation allows the sponsors the ability to identify and evaluate potential risks with the drug and make appropriate adjustments to their clinical development program.
The DSUR expects more information than its predecessors (IND-ARs and ASRs) including patient data from the inception of a project, and could thus take more time for a company to prepare. As with most things, once a process is put in place and becomes familiar, subsequent reports will become smoother to produce.
Points to Remember
- A DSUR should be submitted until the last visit of the last patient in the Member States concerned, as specified within the protocol.
- The data lock point (DLP) for a DSUR reporting period is the last day (or the last day of the month, ICH E2F section 2.2) before the anniversary of the DIBD (Development International Birth Date), the date on which the product was first authorized for testing in humans anywhere in the world. IBD (International Birth Date), the date on which the product was first approved for market anywhere in the world can also be acceptable.
- The first DSUR period should not be longer than 1 year. The DSUR is always submitted on a yearly basis.
- For transitional period: The DIBD and the European Birth Date (EBD) of the previous
- ASR should be aligned in such a way that DSUR periods that are substantially longer than 12 month as well as overlapping DUSR periods are avoided.
- A DSUR is required for Phase IV clinical trials, if only such trials are conducted.
- Submission of one single DSUR is strongly recommended if the same IMP is used in the clinical trials.
- A separate DSUR for a comparator, placebo or non-IMP is not required. However, relevant safety information of the above mentioned drug types should be addressed in the DSURs of the investigational drugs.
- The Investigator Brochure (IB) or Summary of Product Characteristics (SmPC) can be updated during the DSUR reporting period.
Since CDSCO does not require DSUR, for Indian pharmaceutical companies undertaking a global trial for a locally developed drug, Indian regulators will not have real-time update of the drug's developing safety profile, while foreign regulators (such as tripartite countries) having requirement of DSURs will have this information. With the global focus on DSUR, Schedule Y needs to be revised incorporating similar provision of providing cumulative safety updates to the regulators during clinical development phase.
By Carrie Stem, MS, Medical Reviewer
Henrietta Lacks is the human source of the cell line that is today known as “HeLa.” This cell line has been used to develop numerous technologies and advances in cell biology and medicine. The source of the cells is often misidentified as “Helen Lane.” Rebecca Skloot’s book The Immortal Life of Henrietta Lacks gives an excellent overview of the life and family of Henrietta Lacks with the scientific concepts explained in layman’s terms. The socioeconomic and racial issues of the Lacks’ family history are intermixed with chapters of Skloot’s present-day quest to learn as much as she can about Henrietta’s story with the support and assistance of Henrietta’s daughter, Deborah.
However, Skloot also delves into the ethical quandaries of clinical research, and in particular, tissue research. Skloot provides informative descriptions of important events in human subjects research from historical events through recent years, which is very important for the knowledge of the general public. Although the ethical standards for clinical research are very different now than they were during the time of Henrietta Lacks, some of the questions surrounding research remain the same. While the majority of people (scientists or not) would likely agree that informed consent is completely essential, there are many other ethical complexities in research. For example, the question of compensation for tissue donors is frequently mentioned in the book. This is an especially important issue for donors whose tissue has desirable traits for the fields of medicine and pharmaceutical development. If donors should be compensated, how much is a “fair” price? Should donors whose tissue is considered more desirable be compensated more than other donors (since their tissues have more monetary value)? Also, how can tissue donors be adequately educated at the time of donation (such as through an informed consent form) on future investigations and topics involving their stored tissues? This is of particular concern in the age of genetic analyses, and the future will no doubt bring more issues as science and medicine continue to progress.
What are your thoughts? Should tissue donors be compensated based on the “value” of their tissues? Should all be compensated equally? Should they be compensated at all?
Skloot, Rebecca. The Immortal Life of Henrietta Lacks. New York: Crown Publishers, 2010.
By Dr. N. Arulmozhi, MPT, PGDCR & PV, Drug Safety Associate
Circadian rhythms9 are physical, mental and behavioral changes that follow a roughly 24 hour cycle, responding primarily to light and darkness in an organism’s environment. They are found in most living things, including animals, plants and many tiny microbes. Circadian rhythms are produced by natural factors within the body, but they are also affected by signals from the environment. Light is the main cue9 influencing circadian rhythms, turning on or turning off genes that control an organism’s internal clocks.
Circadian rhythms can affect normal diurnal changes (6-PAGE 138-139), sleep-wake cycles, hormone release, body temperature and other important bodily functions.
The biological clocks 8 that control circadian rhythms are groupings of interacting molecules in cells throughout the body. Melatonin (5-PAGE 11) is a hormone secreted by the pineal gland in the brain. It helps regulate other hormones and maintains the body's circadian rhythm. A “master clock” in the brain coordinates all the body clocks so that they are in synch. The release of ACTH (4-PAGE 879) (adrenocorticotropin) by the pituitary gland at the base of the brain is driven by a third hormone that is activated by the body's master clock.
The “master clock” 9 that controls circadian rhythms consists of a group of nerve cells in the brain called the suprachiasmatic nucleus, or SCN. The SCN contains about 20,000 nerve cells and is located in the hypothalamus, an area of the brain just above where the optic nerves from the eyes cross.
AN UNKNOWN ELECTRICAL INSTABILITY IN THE HEART
A fundamental discovery (7-PAGE 18) by the research team led by Case Western Reserve University School of Medicine, United States, uncovers the first molecular evidence linking the body’s natural circadian rhythms to sudden cardiac death.
Ventricular arrhythmias (3-PAGE 10) or abnormal heart rhythms are the most common cause of sudden cardiac death. They occur most frequently in the morning walking hours (2-PAGE 674), followed by a smaller peak in the evening hours. Circadian rhythms are highest level in the morning and lowest level on going to bed at night. While scientists have observed this tendency for many years, prior to this breakthrough, the molecular basis for these daily patterns was unknown.
NEUROPHYSIOLOGY OF CIRCADIAN RHYTHM & STRESS (1-PAGE 4-157)
This discovery will be the first step towards new diagnostic tools and therapies to prevent or treat the occurrence of this fatal event. The research team discovered that a novel genetic factor, “Kruppel-like Factor 15” (KLF15) (7-PAGE NO 18), links the body’s natural circadian rhythm to, and regulates the heart’s electrical activity. A lack or excess of KLF15 causes a loss or disruption in the heart’s electrical cycle and greatly increases susceptibility to arrhythmias.
A lack of KLF15 seen in patients with heart failure, while its excess electrocardiography (ECG) changes such as those seen in patients with Brugada syndrome, a genetic heart rhythm disorder.
“This study identifies a hitherto unknown mechanism for electrical instability in the heart. It provides insight into day and night variation in arrhythmia susceptibility that has been known for many years”.
With this understanding, scientists can propose new patient treatments with the goal of reducing incidences of sudden cardiac death (7-PAGE NO 18). This landmark finding shows that circadian rhythms are an important factor in sudden cardiac death. In addition, it raises the possibility that additional factors may affect that occurrence of sudden cardiac death.
Sudden cardiac death due to electrical instability is the leading cause of death in the United States at 700 – 800 deaths per day(7-PAGE NO 18). It accounts for 10,460 (75.4%) of all 13,873 cardiac disease deaths in persons aged 35 - 44 years old in the U.S. When a person changes daily sleeping habits, the cycle changes accordingly (4-PAGE 880). Further studies are needed to examine the how additional components of the biological clock affect electrical instability in the heart.
- CHATERJEE C.C, “HUMAN PHYSIOLOGY”, 10th edition, 1988, Ashutosh Lithographic Company, Kolkata.
- DAVIDSON, “PRINCIPLES AND PRACTICE OF MEDICINE”, 7th edition, 1996, Churchil Livingstone, New York.
- DESMOND G.JULIAN, “CARDIOLOGY”, 7th edition, 1998, W.B.Saunders, Sydney.
- GUYTON & HALL, “TEXTBOOK OF MEDICAL PHYSIOLOGY”, 10th edition, 2001, W.B.Saunders, Singapore.
- JOHN WALTON, “BRAIN’S DISEASES OF THE NERVOUS SYSTEM”, 10th edition, Oxford university press, Oxford.
- LARRY G. SHAVER, “ESSENTIALS OF EXERCISE PHYSIOLOGY”, 5th edition, Surjeet Publications, Delhi.
- “THE HINDU”, Dated 23 Feb 2012, Bangalore.