MMS Holdings Blog

Are Pharmaceutical Companies Mainstreaming Nutraceuticals?

  

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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. 

References

http://www.raps.org/focusonline/news/newsarticleview/tabid/913/article/2856/warning-letter-targets-product-association-with-search-engine-results.aspx

http://www.forbes.com/sites/scottgottlieb/2013/02/15/fda-regulates-internet-search/

http://www.i2p.com.au/article/nutraceuticals-going-global-mainstream?fullscreen   

http://www.ana-jana.org/nut_info_details.cfm?NutInfoID=9

http://en.wikipedia.org/wiki/Nutraceutical

http://en.wikipedia.org/wiki/FDA

http://www.weighttraining.com/faq/how-much-does-the-average-american-spend-on-supplements

4 Essentials to Colleague Recruitment and Retention in Pharma

  

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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:

1. 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.
2. 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. 
3. 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.
4. 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?

References

1. http://www.salary.com/docs/resources/JobSatSurvey_08.pdf
2. http://www.forbes.com/sites/aileron/2011/09/20/motivating-and-retaining-the-best-employees/
3. http://www.lifescienceleader.com/magazine/past-issues3/item/4304-%E2%80%9Cnice-bike%E2%80%9D-%E2%80%94-the-importance-of-making-meaningful-connections?list=n
4. http://www.diversityjournal.com/3934-best-practices-for-recruitment-and-retention-start-with-corporate-culture/
5. http://www.ngpharma.com/article/Targeting-Top-Talent/
6. http://www.ere.net/2006/09/25/12-best-recruiting-practices-to-copy/

Clinical Trial Disclosure: More “FDA” Needed in Past & Present Acts?

  

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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:

1. 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
2. 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: 

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?

 References

1. Federal Register
2. HHS Delegates FDA Authority to Enforce ClinicalTrials.gov Reporting Requirements
3. Clinical Trials Reporting and Publication, Congressional Research Service for Congress
4. FDAAA Title VIII (PL 110-85, Section 801) Expanded Clinical Trials Registry and Results Database – An FDA Update; Drug Information Association (3^rd Annual Clinical Trials Disclosure Workshop), October 7, 2009.
5. ClinicalTrials.gov Registration and Results Reporting: Updates and Recent Activity. Journal of Clinical Research Best Practices. Vol 7, No. 2, February 2011.
6. BMJ Article on Clinical Trial Reporting Foments Discontent on Capital Hill
7. FDA says study overestimated non-compliance with data-reporting laws
8. Clinical Trial Data Disclosure: The Pace Quickens, Journal of Clinical Research Best Practices, Vol 8, No 10, October 2012

Clinical Disclosure Reporting: Are You Prepared to Meet the Expanding Requirements?

  

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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.

Setting Ground Rules for Medical Writing Document Review

  

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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.

1. 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.
2. 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.
3. 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. 
4. 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.
5. 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.
6. 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.

Circadian Rhythm and Sudden Cardiac Death

  

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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.

BIOLOGICAL CLOCKS

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)}

NEW PATH

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”.

NEW TREATMENTS

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.

EPILOGUE

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.

References

1. CHATERJEE C.C, “HUMAN PHYSIOLOGY”, 10^th edition, 1988, Ashutosh Lithographic Company, Kolkata.
2. DAVIDSON, “PRINCIPLES AND PRACTICE OF MEDICINE”, 7^th edition, 1996, Churchil Livingstone, New York.
3. DESMOND G.JULIAN, “CARDIOLOGY”, 7^th edition, 1998, W.B.Saunders, Sydney.
4. GUYTON & HALL, “TEXTBOOK OF MEDICAL PHYSIOLOGY”, 10^th edition, 2001, W.B.Saunders, Singapore.
5. JOHN WALTON, “BRAIN’S DISEASES OF THE NERVOUS SYSTEM”, 10^th edition, Oxford university press, Oxford.
6. LARRY G. SHAVER, “ESSENTIALS OF EXERCISE PHYSIOLOGY”, 5^th edition, Surjeet Publications, Delhi.
7. “THE HINDU”, Dated 23 Feb 2012, Bangalore.
8. http://en.wikipedia.org/wiki/Circadian_rhythm
9. http://www.nigms.nih.gov/Education/Factsheet_CircadianRhythms.htm

Choosing the Right Clinical Research Organization in 5 Steps!

  

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By Donald F. McLean, MBA, Business & Contracts Associate

Choosing a Clinical Research Organization (CRO) is a daunting task. The number one concern of any pharmaceutical company is getting the product to market on time, the first time. Questions arise. Do you use multiple CROs that specialize in different areas or one CRO that does everything? Do you choose a small or large CRO? What attributes do you look for? Here are five attributes to help you narrow your search:

1. Flexibility - Your CRO should be flexible. Being flexible is synonymous with niche CROs. Why? Because niche CROs are small, agile, and they can be seen as an extension to the internal team and less like an outsider. If quick response is needed, you’ll need a CRO that has a developed quick action process, such as Adaptive Parallel Processing (APP)®.     
2. Experience - Experience is a key factor. Senior leadership at the organization should be built from ex-pharmaceutical industry executives that have proven their success. Similarly, the members of the internal teams should have a certain amount of industry experience as well to better be able to service you, the client. You see this more often in niche CROs. Niche CROs won’t give you a B or C team, they give you the A team consistently, no matter what size company you are. And, when it comes time for that regulatory submission, a niche CRO will go above and beyond to show you that your submission is just as important as the rest.
3. Speed and Accuracy - While drug development may be a lengthy process, when it comes to your CRO you want them to be fast and accurate. Along the lines of flexibility, a niche CRO can adjust speed much more easily than a large CRO due to less stringent and bureaucratic approaches. This is where an International Organization for Standardization (ISO) certification comes in. You’ll want to check to make sure the CRO you choose is ISO 9001 and ISO 27001 certified. These certifications are important to the quality and accuracy of your regulatory submission.
4. Data Control - Your data needs to be clean and be kept clean. Also, ease of access is key. These two things allow you greater control over the project and the direction in which it is headed. A CRO should bring that experience that is necessary for the greatest clarity in your data, and that’s when you want the guaranteed A team that is brought forth in a niche CRO.
5. Regulatory Requirements - When it comes time to take your submission to a regulatory authority, such as the FDA or EMEA, you’ll want a CRO who has an intimate knowledge with the agency. This expertise will help to avoid the common pharmaceutical submission hurdles and help your product get to market on schedule. Each of the four previous items relate to this category. Proven experience with pharmaceutical regulatory requirements is a must.

Flexibility, experience, speed and accuracy, data control, and knowledge of regulatory requirements are five key factors to consider when choosing your CRO. The combination of these qualities will assist them in acting as an internal extension of your team. Many small and large CROs have a good track record for certain reasons, but remember the large ones can be bulky and cumbersome while the small ones can be nimble and proactively focus on your needs. It takes time in choosing the right niche CRO, because out of the hundreds, you need to find the niche CRO that meets your needs.  Once you choose your niche CRO you will notice the proactive approach, cost effectiveness, and greater control that comes with it. Control is always key when your credibility is on the line.

What other things do you look for in choosing the right CRO?

Research to Medical Writing: Transitioning from Bench-Top to Cubicle

  

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By Amanda Beaster, Ph.D., Research Associate

Soon after graduation, I, like many other young researchers, found myself trying to choose from an ever-narrowing pool of opportunities in academic research.  Low funding rates and an increasing number of investigators meant that during my seven grueling years spent pursuing an advanced degree, I watched while seasoned investigators, merit award winners, and departmental chairs lost funding.  In addition to a growing trepidation about ever receiving funding on my own, I was left with this haunting question: Who was I helping?

I believe that basic research is a noble pursuit, and that the majority of great scientific advances have had their roots in such research.  However, I went into science hoping to help the sick and suffering, wanting to play a role in providing new treatments, new therapies, and new cures.  Unfortunately, despite the best efforts of many, I found that there is often an immense gap between the bench-top and the bedside.

So what should I do?  The answer soon made itself apparent:  I would write for the pharmaceutical industry. This industry consistently offers an opportunity to do what I have wanted to do: contribute to the understanding and potentially new treatments, new therapies, and new cures for the sick and suffering.  I decided to use my knowledge of science and technical writing to try to help complete the steps needed when moving a compound from an investigational product to a new drug.

The transition has been surprisingly painless, made easier by the training program at MMS Holdings Inc.  I have learned more about word processing in the last month than I did in the previous decade, and I am constantly amazed by the amount effort that goes into every syllable of the documents produced here.  Although the day-to-day aspects of the job are completely different such as business dress instead of lab coats and pens instead of pipettes, I am finding that many of the traits I learned in the lab are equally necessary here.  Relentless attention to detail, consistency, and the ability to apply the scientific process are just a few of the laboratory-acquired skills that I have already employed in my short time in medical writing.

I owe a lot to academic research, it was my proving grounds and taught me how to be a scientist, but now, typing away in my cubicle, I know that the effort I put forth in using all of my education will result in improving the health and happiness of others.

Case Study: Advisory Committee Briefing Documents

  

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THE CHALLENGE: Compile a Briefing Book for an Aggressive FDA Deadline

A biologics pharmaceutical company was in need of a advisory committee briefing book to present to an FDA Advisory Committee. However, the deadline for submitting the book was too close for the company to pull together the necessary information using only their internal resources. To turn the project around quickly and to meet their rapidly approaching deadline, they brought MMS on board to provide additional expertise.

MMS SOLUTION: Assemble a Rapid Response Team to Quickly Get the Job Done

As part of our Adaptive Parallel Processing approach, MMS put together a Rapid Response Team to generate the briefing document. Consisting of experienced and skilled experts in the various areas related to the project, the team immediately began work on the book in conjunction with supporting slide decks and an external mock-panel. The goal was not only to develop a briefing book in the allotted timeframe, but to also ensure that it reflected the latest organizational thinking and complement the slide deck and associated arguments.

THE OUTCOME: Briefing Book Completed and Delivered On Time

Despite the aggressive deadline and a blizzard that essentially halted the company’s operations for three days, MMS delivered the briefing document in advance of the deadline with full quality checks. The company successfully presented the book to the FDA Advisory Committee on time, avoided spending additional time and money on would-be delays, and their drug was ultimately approved.

Clinical BioStatistician/Programmer: A Day in the Life

  

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By Justin Sjogren, MS, Clinical BioStatistician/Programer

[Note: In August 2011, one of my former Statistics professors at GVSU asked me if MMS would be interested in having a booth at GVSU Statistics Career Day, and if I would be willing to give a talk. My presentation focused around my job as a statistician/programmer in the pharmaceutical industry and was geared towards undergraduate and graduate students who were interested in learning more about what a career in statistics is like from the perspective of a former student. The presentation is summarized below.]

Statisticians play an important role in many phases of the clinical trial process, beginning at the design stage and progressing through the final analysis. Statisticians keep the big picture in mind and key strengths include their ability to ask good questions, or ask why a particular decision was made and how best to ensure that each question is worthwhile and useful. They provide input early on in trial development about things such as the type of trial design, randomization considerations, and sample size calculations, which identify the number of subjects needed for a successful trial. All these items help to save the sponsor in time and cost.

Another key responsibility of the statistician is to write the Statistical Analysis Plan (SAP). This regulatory document tells specifically how the analyses will be performed and what will be reported in the final tables. This is where the statistician can think more deeply about how to answer the research question through the appropriate analyses.

During the clinical trial and as subject data starts being made available, clinical programmers will begin producing draft summary tables and statisticians will begin looking into the draft output to ensure everything is in order. In a blinded clinical trial, the treatment group assignments remain unknown until trial completion, so in the datasets, programmers assign subjects to ‘dummy’ treatment groups, which allows them to produce tables that will look just like the final output, only the treatments that the subjects are assigned to are not real. This allows for the study team to have a look at the tables and provide comments prior to the final analysis.

Some clinical trials will have interim analyses, which is a special type of analysis done after only a percentage of the subjects have been enrolled. Often times, early in drug development, the sponsor may be curious about which dose levels are most effective and most well-tolerated, so they will assess this at some point (maybe after 50% of the subjects have been enrolled) during the trial rather than waiting until all subjects have been enrolled. This allows the sponsor to drop doses or re-allocate to certain dose groups if any safety or tolerability issues are seen. This can be tricky however, because the trial is still ongoing and the core study team needs to remain blinded, so an independent group is often utilized to help aid in these decisions. For example, an independent (separate from the sponsor company) statistician will typically be identified to ‘unblind’ the study and perform the required unblinded analyses. Often times the statistician will submit the results to a panel of experts (called a data monitoring committee) to review and decide if or what study modifications may be needed.  These may be due in some way to a particular safety concern that may even lead to trial termination or suspension. These decisions are communicated to the sponsor’s upper management.

In a more traditional clinical trial, when all subjects have completed, the database is locked, the study is unblinded, and statisticians and programmers are charged with creating the final tables, listings and graphs. If the analysis calls for any inferential statistics (such as models or statistical tests), the statisticians will typically create these tables. These tables are sent to the medical writers for incorporation into the clinical study report. Then, statisticians are available to the medical writers for any technical questions regarding the tables

Statisticians can have a wide variety of duties and responsibilities, but below are some common traits a good statistician will possess:

• Clear and concise writer – there are no style points when writing SAPs, but clear writing is still very important in providing a how-to for another statistician or in providing statistical rationale for statisticians and non-statisticians alike
• Understanding of statistical tools such as SAS® – having this skill is extremely helpful for investigating issues, completing analysis and validation, etc.
• Interpretation of statistical concepts to non-statistical audiences
• Learn from experiences – build off of what has and has not worked in the past
• Strong attention to detail
• Thoroughness