MMS Holdings Blog

The Year in Review: The Most Exciting Advances in Neuroscience in 2014

Posted on Tue, Jan 13, 2015 @ 10:00 AM

By Charlie Taylor, Regulatory Writer and Drug Development Consultant, MMS Holdings

Neuroscience continues to advance rapidly, with tens of thousands of new peer-reviewed articles each year. Several findings stood out to me in 2014 as being relevant for neurology and psychiatry drug discovery and development. This summary scratches the surface…

Clinical Neuroscience Studies:

  • Cognitive deficits in schizophrenia are a huge unmet challenge because existing antipsychotic drugs do little to help impaired memory, planning for the future and “emotional IQ.”  Santarelli and colleagues, in a trial with schizophrenia patients (Umbricht, Keefe et al. 2014), found that RG3487, an alpha-7 specific nicotinic partial agonist, improved thinking deficits (Negative Symptom subscore) in a subset of schizophrenia patients. Treatment effects were large (about 25% of the total negative symptoms score) and dose-related. These results are very encouraging for future treatment of schizophrenia negative symptoms and also may explain why more than 60% of patients with schizophrenia smoke.
  • Alzheimer’s disease is a huge healthcare challenge that, despite intense drug discovery efforts for over 30 years, remains mostly untreatable. Behavioral agitation, mood swings and aggression in Alzheimer’s are a particular burden to health care providers. Physicians have been criticized for overusing major tranquilizers (antipsychotic drugs) to reduce agitation. Although effective, such treatments sedate patients and compromise memory and thinking. In contrast, a new formulation of dextromethorphan plus quinidine (Nuedexta®) reduced agitation in Alzheimer’s patients without sedation. Dextromethorphan is the active ingredient in most over-the-counter cough suppressants and quinidine is an older cardiovascular drug now used in small amounts to greatly reduce dextromethorphan metabolism. In apparent reaction to the clinical trial news, Avanir stock increased in value 3-fold and Otsuka Pharmaceuticals announced plans to acquire Avanir for about $3.5 billion.
  • New drugs intended to prevent the progression of early Alzheimer’s have been the focus of dozens of drug discovery efforts over the past 20 years. A review of anti-amyloid treatments for Alzheimer’s disease (Karran and Hardy 2014) critically discussed results from 6 different drugs that completed randomized placebo-controlled clinical trials. Overall results were disappointing, with no clear indication that any treatment slowed the advancement of disease. This leaves the field in doubt as to whether any future treatment to reduce amyloid aggregation in the brain will ever successfully treat Alzheimer’s disease.


Laboratory Basic Neuroscience Studies:


  • The 2014 BRAIN Initiative promotes collaboration across U.S. agencies, academic laboratories and the private sector to increase understanding of the human brain using techniques such as large electron microscope serial section reconstructions and large-scale computer simulations that are costly and labor intensive. This initiative supports large studies such as the Human Connectome Project and recording methods that monitor hundreds of brain neurons simultaneously. Older techniques such as single-neuron electrical recordings, although very useful, have been likened to analyzing a football game by watching the responses of a single fan in the stands. Additional steps forward in understanding brain function will require progressively bigger advances in technology.
  • A review of genes that contribute to psychiatric disease (Gratten, Wray et al. 2014) showed that  psychiatric and neurological disorders usually result from many different genes that each contribute a very small risk for disease. For example, over 125 known genes contribute to schizophrenia, 20 contribute to Alzheimer’s disease and 8 to bipolar disorder. No genetic risk factors are known for ADHD, anorexia, major depressive disorder or obsessive-compulsive disorder. In schizophrenia, no single gene contributes more than 4% of the overall risk for disease. In contrast, overall genetic heritability of schizophrenia, major depression and autism are each between 40% and 80% (judged by family tree analysis). Therefore, although heritability of psychiatric disease is relatively high, identification of single genes seems unlikely to uncover future treatments that are useful for the entire disease population. The remaining non-genetic risk of disease is presumed to be caused by environmental factors and de novo mutations and gene duplications that are not inherited. In summary, the hope that sequencing the human genome would lead directly to useful medical treatments for common psychiatric diseases seems unrealistic.
  • John O’Keefe, May-Brit Moser and Edvard Moser shared a 2014 Nobel Prize for their work to describe how neurons in the hippocampus and entorhinal cortex determine position and enable spatial navigation. They discovered “place cells” and “grid cells” that react to visual cues when an animal occupies one spot or moves through 3-D space. This system has been called the brain’s GPS and it also is used to organize memory of sequences of events. Their approach is one of the first to yield new understandings on the mechanisms of abstract thinking that is not directly linked to sensory or motor function.
  • New results helped understand how the brain manipulates the “good or bad” associated with memories. Tonegawa and colleagues at MIT (Redondo, Kim et al. 2014) manipulated a set of neurons in mouse hippocampus and changed the “polarity” of memories from bad (a specific place where mice received foot shocks) to good (a place where mice were exposed to sexually receptive female mice) and vice versa. This was done by selectively activating neurons in the dorsal dentate gyrus of the hippocampus with light pulses that activated neurons while mice were exposed to either positive or negative reinforcement. These results give hope that specific future treatments for post-traumatic stress syndrome and other negative memories might be discovered in humans.
  • During 2014, evidence continues to emerge that sleep disturbances may cause memory problems seen with Alzheimer’s, aging, depression and schizophrenia…And sleep disturbance may contribute directly to the progression of Alzheimer’s disease. These findings suggest that drug treatments or lifestyle changes that specifically improve sleep quality (for example, increasing phase 4 or deep sleep and reducing sleep disruptions) may improve cognitive deficits and also prevent Alzheimer’s disease progression.

o   Artificially increasing a natural protein in the hippocampus of mice (phosphorylated eukaryotic translation initiation factor 43 binding protein or 4EBP2) helps retain spatial memories that otherwise degrade with sleep deprivation. This indicates that the mammalian target of rapamycin (mTOR) biochemical pathway is compromised with sleep loss, causing memory deficits (Choi, Davis et al. 2014). The mTOR pathway is activated by many different stimuli that each cause new transcription of DNA and synthesis of new proteins inside of neurons.

o   Sleep disturbance also may contribute directly to disease progression in Alzheimer’s disease. Maiken Nedergaard and colleagues at University of Rochester (Xie, Kang et al. 2013) found that fluid flow within the brain increases up to 10-fold with slow-wave sleep compared to waking in rats. They propose that metabolic byproducts and amyloid protein accumulate in brain with lost sleep, and this contributes directly to Alzheimer’s disease. In a follow-up paper (Kress, Iliff et al. 2014) they found that brain tissue clearance of amyloid protein is impaired 40% in aged mice compared to young mice. They also showed that the glial ion channel aquaporin-1 is lost in astrocytes of aged mice. The same group (Iliff, Chen et al. 2014) found that head trauma causes glial scars that substantially reduce brain fluid flow. It has long been known that head trauma is a major risk factor for subsequent Alzheimer’s, and this is the first study to directly suggest why.

  • (El-Boustani and Sur 2014) used electrophysiology of single brain neurons and calcium imaging of a large network of neurons together with genetically-engineered light stimulation (optogenetics) to study inhibitory GABA interneurons. The GABA neurons either caused subtractive or divisive inhibition at their target cells, depending on the timing of inhibition with relation to excitation in the neurons they innervate. This finding will provide a better overall understanding and better modelling of neuronal networks in neocortex.

Overall, these advances in neuroscience underscore a couple of conclusions. Firstly, many approaches to treating Alzheimer’s and other serious mental disorders, although based on solid logic and promising results in animal models, have failed miserably in clinical trials. This, unfortunately, is a common fact of life for drug discovery. Secondly, promising findings often emerge from approaches that at first seem trivial (such as improving sleep quality in schizophrenia or Alzheimer’s disease). Undoubtedly, as progress continues toward understanding the brain and mind, future therapies for common disabling diseases such as depression, schizophrenia and Alzheimer’s will emerge that are much different from those in use today. 


1. Choi JH, Davis EJ, Havekes R and Abel T (2014). Restoration of phosphorylated eukaryotic translation initiation factor 4E binding protein 2 (4EBP2) in the hippocampus rescues memory impairment due to sleep deprivation Soc. Neurosci. Abstracts 291.07.


2. El-Boustani S and Sur M (2014). Response-dependent dynamics of cell-specific inhibition in cortical networks in vivo. Nat Commun 5: 5689.


3. Gratten J, Wray NR, Keller MC and Visscher PM (2014). Large-scale genomics unveils the genetic architecture of psychiatric disorders. Nat Neurosci 17(6): 782-790.


4. Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L, Singh I, Deane R and Nedergaard M (2014). Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci 34(49): 16180-16193.


5. Karran E and Hardy J (2014). A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. Ann Neurol 76(2): 185-205.


6. Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, Xie L, Kang H, Xu Q, Liew JA, Plog BA, Ding F, Deane R and Nedergaard M (2014). Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76(6): 845-861.


7. Redondo RL, Kim J, Arons AL, Ramirez S, Liu X and Tonegawa S (2014). Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature 513(7518): 426-430.


8. Umbricht D, Keefe RS, Murray S, Lowe DA, Porter R, Garibaldi G and Santarelli L (2014). A randomized, placebo-controlled study investigating the nicotinic alpha7 agonist, RG3487, for cognitive deficits in schizophrenia. Neuropsychopharmacology 39(7): 1568-1577.


9. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R and Nedergaard M (2013). Sleep drives metabolite clearance from the adult brain. Science 342(6156): 373-377.




Tags: Year in Review

One Small Secret to a More Successful Briefing Document

Posted on Tue, Sep 23, 2014 @ 08:00 AM

By Ben Kasper, Global Submissions Manager

Many of us who work in the pharmaceutical industry can recall excitedly explaining aspects of our science to friends and family.  Perhaps the discussion took the form of a conversation of food effect around the thanksgiving table, or a detailed breakdown of a mechanism of action to a curious high school biology student.  The questions that arise from discussions are often illuminating—allowing us to see science in a different way and helping us explain it more convincingly in the future.  While discussions with the FDA frequently invoke more anxiety than dinner table conversations, they share one important similarity:  both represent unique opportunities to convey the meaning, challenges, and direction of our work in a broader context, and to a broader audience, than we would normally do within our development teams. The FDA is also key to accepting our conclusions about the science for an effective end-game.


In any communication, proper emphasis on structure and context adds value and is opportunity realized.  When communicating with the FDA, our most powerful tool to build structure and provide context is the briefing document.  The FDA suggests inclusion of 10 types of critical information in the briefing document (Table 1).  Striking the right balance of detail between the related sections is a challenge.  Conceptually, it helps to think of the briefing document as having two major sections:  the background (items 1-9) and the supportive data section (item 10).  The background represents the ability to concisely tell a story that is complete in itself, while the supportive data is the base that allows deeper questions to be addressed quickly and with authority. 

A strong background and thorough supportive data will result in a good briefing document, but not a great one.  To achieve a great briefing document the background sections must also anticipate the reviewer’s questions and direct them to the supportive data in order to answer these questions at the appropriate level of detail.  Here, it helps to have a strong, knowledgeable reviewer outside of the development team to conduct a high level global review.  This reviewer should have sufficient scientific experience and background to comment on the structure and context of the briefing document with a perspective similar to that of an FDA reviewer. It provides a non-passionate objective review. Often, when we are close to the development of a compound, we do not see some of the issues as being questionable even though the science is thorough. A fresh pair of eyes provided by such a review tends to focus on areas of inconsistency, ambiguity, and excessive jargon that accrue in multiple author/draft cycle documents.  They will generally find instances where long searches in the supportive data are required to address questions arising in the background sections.  Eliminating these instances saves time for both the sponsor and the FDA, allowing meetings to focus on content rather than clarification.  Just as an unanticipated question from a friend or family member can lead to new ways of seeing our work, an unanticipated question from an outside reviewer reveal more effectives ways of conveying our work to the agency.

When meeting with the agency, you cannot choose your review team.  One way to prepare for this is to have a trusted reviewer not directly involved in the project to review your briefing document.  With our strong emphasis on science, the medical writers and strategists at MMS Holdings can provide a level of support similar to a trusted outside reviewer, leading to unexpected insights and improved preparation for your most important FDA interactions.

Probiotics – Food for Thought?

Posted on Tue, Sep 09, 2014 @ 08:00 AM

Stephanie Hreha, MS, Technical Manager, Medical & Regulatory Writing

Probiotics Blog ImageIn your food, at your doctor’s office, in your body… these microorganisms seem to be supplementing our diets, supplementing our medications, and inhabiting our daily lives.  But does anyone really know what they are or who’s monitoring their use?  Google advertises brand name probiotics with claims to be gastroenterologist recommended and clinically tested.  Further down the page, search results produce definitions of probiotics from sites such as WebMD and Wikipedia declaring the health benefits, listing side effects, supplements, and foods containing probiotics.  Dr. Oz provides a fact sheet and your local pharmacy offers free shipping.  Next come the claims, from reputable sources, that probiotics are being used to treat everything from the common cold to depression.  While we have spent most of our lives shying away from germs and sanitizing everything in our paths, we are now re-introducing ‘good’ bacteria back into our bodies.

In 2002, a group of experts from the Food and Agriculture Organization of the United Nations and the World Health Organization convened to answer the very question, “what are probiotics?”  They defined probiotics as “live microorganisms administered in adequate amounts that confer a beneficial health effect on the host.”  Although scientifically sound, this definition blurs the lines of clear paths that regulatory agencies, such as the United States Food and Drug Administration (FDA), have established for the use of foods, drugs, and biologics; microorgansisms can fit into any one of these categories.  According to the FDA, the intended use of a substance and the claims one intends to make regarding the substance determine how it is regulated.  Probiotics used to diagnose, cure, mitigate, treat, or prevent disease is a drug and a biological product, are regulated by FDA’s Center for Biologics Evaluation and Research.  Probiotics used as dietary supplements or food ingredients are regulated by the FDA’s Center for Food Safety and Applied Nutrition.  For approval of drug or biologic products, safety and efficacy must be established.  This is not required for dietary supplements.  Which pathway would you choose?

In November 2013, DuPont Nutrition & Health received confirmation from the FDA that the probiotic strains in its Bifidobacterium lactis range were safe and suitable for use in all food products and dietary supplements.  Establishing safety and efficacy through the traditional investigational new drug pathway was not required, yet their product is legally reaching consumers.  Many such products are making a name for probiotics as ‘miracle drugs’ without the average consumer fully understanding the difference between a supplement and a drug if recommended by physicians or self-prescribed as an over the counter ‘treatment.’  Unless all probiotics are lumped into a single category as either a food, drug, or biologic,  would manufacturers be able to tailor their claims to tip toe around the rigorous approval pathways for drugs and biologics, while still getting their product on the market for widespread use?  Or is this a decision better left to the FDA?

Case Study: MMS Support for Small Pharma

Posted on Tue, Sep 02, 2014 @ 08:00 AM

Challenge:  Sponsor needed Regulatory Project Management for Phase 2/3 Program

A small pharmaceutical company had the need for regulatory project management and regulatory document management to support their Phase 2/3 program. The sponsor selected MMS because of the strength of our teams, infrastructure, and regulatory experience.

MMS Solution:  Provide Regulatory Team to Manage the Phase 2/3 Project

MMS provided a regulatory team, including regulatory project manager, regulatory operations specialist, document management and regulatory writer, to manage the project. Our regulatory project manager led the project team responsible for requesting and planning for the End of Phase 2 meeting. The MMS regulatory writing team completed numerous documents for this program and submission including Investigator Brochure (IB) updates, briefing documents, Phase 3 protocol along with Special Protocol Assessment (SPA) and other components within shorten timelines. MMS attended the FDA meeting, acted as the regulatory lead, prepared the meeting summary, and proposed actions resulting from this meeting.

Outcome:  Completed Phase 2 Regulatory Tasks Prior to the Targeted Date

MMS completed the transition of regulatory tasks from the sponsor team within the requested timelines and immediately began working on clinical protocol and agency briefing materials. MMS timelines allowed the sponsor to schedule the end of Phase 2 meeting earlier than the targeted date. The successful End of Phase 2 meeting resulted in the clarity needed to start the Phase 3 study.

Tags: FDA, Regulatory Team, Regulatory Project Managment, Regulatory Document Management, operations, investigator brochure, Special Protocol Assessment, Phase 2/3

The COMPETE Act of 2014 – Extending the R&D Tax Credit

Posted on Tue, Aug 26, 2014 @ 08:00 AM

By: Michael Gleeson, Marketing & Communications Manager

Senator Tom Carper (D-Del) recently introduced the Competitiveness and Opportunity by Modernizing and Permanently Extending the Tax Credit for Experimentation Act of 2014, otherwise known as the COMPETE Act of 2014, in Congress.  This bill seeks to amend the Internal Revenue Code of 1986 to increase and make permanent the alternative simplified research credit.

Supported by the Association of Clinical Research Organizations (ACRO) and Biotechnology Industry Organization (BIO), the COMPETE Act of 2014 is designed to encourage the private sector to develop innovative products and services that grow the economy, create jobs, and enhance our daily lives.  It has four primary objectives:

  1. Make the Research and Development tax credit permanent.
  2. Increase the credit to 25 percent of qualifying research investments.
  3. Allow contract research organizations to claim up to a 35 percent portion of the credit.
  4. Direct private funding to profitable start-ups by allowing small research companies to claim the tax credit.

Transformative research projects with strong long-term economic growth  potential could earn additional targeted, limited R&D bonuses.

The bill was introduced by the Senate Finance committee in response to recent corporate inversion transactions. Organizations are acquiring foreign companies and incorporating the new entity in a foreign country with lower taxes, which prevents the Internal Revenue Service (IRS) from taxing overseas earnings.  According to Bloomberg, 12 U.S. companies have reincorporated in low-tax countries since 2012 and eight more plan to do so in the coming year (Mider, 2014).  The COMPETE Act seeks to strengthen and improve incentives to invest revolutionary, high-value research (Carper, 2014) and reduce inversion transactions.

The COMPETE Act’s biggest roadblocks are determining where the money for the increase rate will come from and the decision to make the tax credit permanent.  In May, the House of Representatives passed a similar bill, the American Research and Competitive Act of 2014 (H.R. 4438), to extend the research and development tax credit.  While both parties support extending the R&D tax credit, which has been renewed nine times since it was initially enacted in 1981, Senate Democrats and President Obama strongly opposed adding the $156 billion cost to the deficit without offsetting the tax credit.  The COMPETE Act of 2014 will face a similar challenge unless these issues are addressed.

Congress is expected to vote on the COMPETE Act of 2014 in September 2014.

Work Cited

American Research and Competitiveness Act of 2014, H.R. 4438, 113th Cong. (2014). Print.
COMPETE Act of 2014, S. 2715, 113th Cong. (2014). Print.
Mider, Zachary R. "Tax Inversion: How U.S. Companies Buy Tax Breaks." Bloomberg. 18 July 2014. Web.
Senator Tom Carper (D-Del.), (2014). Sen. Carper Introduces COMPETE Act to Boost Research & Development.

Tags: COMPETE Act of 2014, American Research and Competitive Act of 2014, research & development, R&D, Congress, tax credit, permanent

Five Great Reasons to Work at MMS Holdings Inc.

Posted on Tue, Aug 19, 2014 @ 08:00 AM

By: Samantha Foksa, Human Resource Associate II

Working in Human Resources, I perform a wide variety of tasks. The one thing I love doing most in my position is interacting and sometimes meeting our colleagues before they join our company. I have the opportunity to tell them why I love working for MMS and why they will too. Anytime I am asked the question, “Why do you like to work for MMS?” I never have to pause to think. I could name many reasons why I love coming to work every day, but here are the top five:

1.  The Atmosphere

We are a mid-size company that operates like a close-knit family.  Although we have colleagues located all over the world, when we reach out to each other it seems like we are talking to friends who have known each other for years. On every colleague’s first day, we send a welcome note to the entire company letting everyone know we have a new colleague.  The note includes some background information that usually sparks a connection with their new peers. We also keep a colleague slide deck with our pictures, our education, work experience, and some hobbies. Many of us attended the same colleges, worked for the same companies, and have similar interests.  It’s the small things that help us forge relationships regardless of where we are located.

2.  The Opportunity

At MMS, we have a variety of experience levels. We hire colleagues who have over 20 years of experience and some that have none. At the time of hiring, colleagues are assigned a mentor to help them learn and grow. This allows experienced colleagues to share their insight and knowledge and teach techniques to our less experienced teammates.

It’s great to look around and see colleagues who started here as Interns and Research Associates get promoted multiple times, turn into senior level colleagues, managers, or senior managers. MMS also has all colleagues fill out a goals form every year. These goals are discussed in one-on-one meetings and designed to help colleagues to move up the career ladder. We also provide colleagues with opportunities to attend professional trainings and seminars. Whether you are just starting out in your career, or many years in, MMS has opportunities for personal development and growth.

3.  The Team Feeling

One of the things we are very proud of at MMS is our team feeling. We are all part of one big team, and many small ones. We have teams for departments, client projects, and special interests.  Having many departments and having colleagues located all over the world, it would be hard to give everyone the opportunity to interact on a normal basis without creating teams.   At the beginning of the year, our Senior Leadership team holds a Year Beginning Meeting.  As a team, we review the previous year and discuss goals for the new year.  Each team plays an active role in the design process.  We have also created an exchange program where our colleagues from our India offices or Europe offices travel back and forth to allow us to meet each other.  The exchange program keeps that “one big team” feeling alive by exposing colleagues to new cultures and different office settings.

4.  The Company Events

We host a wide variety of company events throughout the year. The last Friday of every month we have a “Game Day” where all of the onsite colleagues get together to eat lunch and play games. In the spring, we have a bowling event where the company provides pizza, pop, and two games of bowling for an afternoon. In the summer, we have a company BBQ picnic where the company provides BBQ style food and we all get together under a pavilion and play games or hang out outside for an afternoon. In the fall, we host an annual Scientific Symposium that allows our talented team members and outside speakers to come to MMS for a full day of education sessions, trainings, and lunch. We also have a fall pot-luck and costume party to celebrate Halloween.  In the winter, we host a holiday party where our Audio/Video committee shows a video recapping all of the company events that happened throughout the year.

5.  The Trainings

At MMS, we are big on training and development. With the recent implementation of our Learning Management System, we spend less time worrying about keeping training records straight and more time focusing on personal development. We have two training coordinators dedicated to ensuring our trainings are up-to-date and relevant for the work that we do. Training is done not only at the time of hire, but throughout the year. Some training is done individually by reading Standard Operating Procedures and Work Practices and other training is done in a classroom setting so colleagues can get together and learn in a group. This also is an opportunity for colleagues who have a lot of experience or knowledge in certain areas to show what they know to the rest of the company.

Spending 40 hours of a week (2,080 hours in a year) at work, you have to like what you do and where you are. I am proud to say that after almost three years, MMS continues to provide many reasons why I would not want to spend my time anywhere else! 

If you are interested in becoming a part of the MMS Team, click here to submit your CV.

Tags: Work, Career, Atmosphere, Opportunity, Team Feeling, Company Events, Trainings

Case Study: MMS Support for Epilepsy Submission

Posted on Tue, Aug 12, 2014 @ 08:00 AM

Challenge:  Mid-sized Pharma Requests Help  Integrating Data for Agency Presentation

A mid-sized pharmaceutical company located in the Midwest was planning for a New Drug Application (NDA). Concerns were raised regarding the feasibility of this submission given the large volume of data requiring conversion into an electronic format and integrated for an agency presentation.

The epilepsy submission included more than 40 studies worth of data from a wide variety of sources in various formats.  Limited data collection standards were in place and electronic databases were largely not available when some of these trials were completed. In some cases, source data needed to be recreated from Clinical Study Reports (CSR) listings or paper Case Reports. This data now needed be prepared, integrated, analyzed, and summarized.

MMS Solution:  Develop Mapping and Integration Plans to Incorporate the Data

The MMS team was responsible for developing a mapping and integration plans to take the outdated data and complete the following tasks:

  • Complete data transfers from a variety of sources
  • Complete data abstraction, dual data entry, and conversion of data to regulatory standards
  • Create an integrated database for submission, review, and code adverse events and medications
  • Create analysis datasets, tables, listings, graphs, and patient profiles for data review and summary

The project was large in scope and timelines were compressed to meet the promised NDA target submission timelines.

Outcome:  Create an Integrated Database for Submission

MMS created a fully integrated database for submission. In addition, MMS provided all raw data, converted Study Data Tabulation Model (SDTM) data, adverse events, medication coding information, and all validation quality documentation to the client. The project was completed on time for the submission and was completed within the planned budget.

Tags: pharmaceutical, csr, sdtm, New Drug Application, NDA, epilepsy, Clinical Study Reports, Data integration, Study Data Tabulation Model

Whitepaper Preview: 505(b)(2) NDA: Navigating the Regulatory Pathway

Posted on Tue, Aug 05, 2014 @ 08:00 AM

By Wendy Bezotte, MBA, PMP

describe the imageReview and Approval of new drugs by the Food and Drug Administration (FDA) is the foundation of drug safety in the United States. Despite this, a number of prescription and over the counter drugs are marketed in the US without FDA approval, often unknown to the patients and health care providers who take and prescribe them. Typically, these are drugs that came to the market prior to the monumental 1962 Food and Drugs Act amendment and, for a variety of historical reasons, have not met the modern standard of scientific evidence for favorable risk/benefit established through this legislation. In recent communications, the FDA has made it clear that historical justifications for the marketing of unapproved drugs will no longer be accepted, and all currently marketed drugs must meet modern scientific and medical standards. It is the stated goal of the FDA to subject all marketed unapproved drugs to immediate enforcement action “at any time, without prior notice”.

For companies marketing unapproved drugs, the question is not whether enforcement will occur, but when will it occur. According to the FDA, the agency has removed numerous unapproved drug products from the market in 17 different drug classes since 2006. To avoid enforcement action and possible removal from the market, the FDA is urging companies that market unapproved drugs to submit New Drug Applications (NDAs). Thus, the first step toward compliance is to understand the purpose, content, and evidentiary standards of the NDA.

The purpose of an NDA is to provide FDA reviewer(s) with enough information to reach the following key decisions:

  • Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks;
  • Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain;
  • Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity.

In order for the FDA to make these determinations, the NDA must tell the marketed unapproved drug's entire story, including results of pre‐clinical testing (animal studies), results of clinical testing (human studies), information on structure and composition, how the drug behaves in the body, and how it is manufactured, processed and packaged.

Sponsors of marketed unapproved drugs must determine the most economical path for an NDA approval based on the ability to leverage all available supportive data. This data need not come solely from studies conducted by the application holder. Instead, the marketed unapproved drug’s clinical history can be taken into account along with the regulatory status and composition of relevant reference drugs and the quality/quantity of available published and sponsor derived data.

The 505(b)(2) NDA whitepaper will:

  • Explain the pros and cons of the different types of NDAs
  • Outline the pathway for the 505(b)(2) submission
  • Explain how strategic partnering will lessen the burden of getting FDA approvals

To download and read the rest of this whitepaper, click here!

Tags: regulatory documents, regulatory submissions, NDA submission, fda submission process, regulatory pathway, FDA, fda approval process, accelerated approval regulations, new drug application regulations, whitepaper

Prescription to OTC Switch – Regulatory Pathways

Posted on Tue, Jul 29, 2014 @ 08:00 AM

describe the image

Recently, we reviewed the regulatory considerations, criteria, and strategies organizations should evaluate when transitioning a prescription drug to an Over the Counter (OTC) drug in the United States.  In order to make the transition to OTC, organizations also need to have a fundamental understanding of the regulatory pathways and choose the appropriate pathway for their product.  There are two ways to register an OTC in the US, OTC Monograph and New Drug Application (NDA).

OTC Monograph System

The OTC Monograph is a regulatory pathway for bringing an OTC to market without requiring FDA evaluation or approval prior to marketing.  It was established as part of the OTC Drug Review in 1972 and sets the guidelines for each therapeutic category (ingredients, indications, doses, formulations, labelling, and testing). 

Registration via the OTC monograph process is a viable option if the active ingredients are generally recognized as safe and effective (GRASE).  According to the FDA, a drug must meet three criteria to be considered GRASE:

  1. The drug must have been subjected to adequate and well-controlled clinical investigations that establish the product as safe and effective
  2. Investigations must have been published in scientific literature available to qualified experts
  3. Qualified experts must generally agree that the product is safe and effective

Any marketed product that deviates from the OTC monograph conditions is considered a new drug and will require FDA approval.  OTCs that were marketed after the inception of the initial 1972 rule and have new conditions are not eligible for inclusion and must follow the NDA pathway.

The FDA is currently reviewing the OTC monograph system and may finalize the Tentative Final Monographs (TFM) at any given time.  When marketing a product under TFM, the sponsor would need to bring the product into compliance with the new conditions in order to continuing marketing the OTC.

New Drug Application

If the product does not meet OTC monograph requirements, a New Drug Application will be required to switch a prescription drug to OTC.  The NDA must be supported by safety and efficacy evidence such as information from previous regulatory filings, post marketing surveillance, safety databases, and literature reports.  Based on this information, the FDA will determine if the prescription product restrictions are no longer required.

New safety and efficacy data from controlled clinical trials are included if the OTC indications and strength differ from the prescription product.  Safety is usually well characterized in the prescription drug’s NDA, but OTC safety questions do need to be addressed:

  • Is the prescription drug’s safety characterization applicable to the much broader OTC population?
  • Are there any side effects that could worsen or become more frequent without professional supervision?
  • Is OTC availability more likely to delay a diagnosis or treatment of a more serious underlying condition?

Efficacy studies may also be warranted in certain situations:

  • The OTC population differs from the population studied to support the prescription indication
  • The demographic profile of the prescription drug cannot be generalized to a wider OTC population
  • The OTC dose or indication differs from the Rx dose indication
  • Standards for demonstration of efficacy are not the same as the prescription drug clinical trail

Do you have a prescription drug ready to make the switch?  We can help.  Contact us for additional information on the regulatory pathways.

Tags: regulatory pathway, OTC, Over the counter drug, FDA, OTC Monograph, OTC Drug Review, GRASE, New Drug Application, NDA

Using Heat Maps in Pharmaceutical Data Analysis

Posted on Tue, Jul 22, 2014 @ 08:00 AM

By Fan Wang, MS, Associate Biostatistician

The Heat Map, broadly used in various fields of study, is an efficient way to convey an abstract concept or a large amount of information via graphical figures through which data patterns (or the lack of) can quickly emerge and be analyzed. It consists of a colored base image body and two separated dendrograms (optional) at the top and left side respectively. Individual numerical values in the dataset are transformed into colors for representation. Columns and rows are clustered by similarity, with highly correlated values shown in similar colors and less correlated (or uncorrelated) values shown in contrasting colors. Of course, the clinical programmer can choose to customize the coloring scheme.

Heat maps also rearrange data columns and rows of a matrix so that highly correlated values are shown closer than those less correlated. Hierarchical clustering is represented by the dendrogram showing the level of similarity at the top or left.  

In clinical studies or pharmaceutical data analysis, use of a heat map helps to move easily visualize the correlation of patients or symptoms etc. Thus, in the application of selecting a large number of variables, the dendrogram of a heat map gives a comprehensive view of variable similarity. A reasonable cutoff decision can be made by balancing the correlation within and among subgroups, size of largest subgroup, and purpose of study. 

In the case of dimension reduction, when the clinical dataset is large and variables are highly correlated, the selection of one variable or combination of all variables (summation or average) from each subgroup could be applied due to similarity within (for example, early, middle and late onset insomnia and hypersomnia could be a subgroup in the study of depression classification). In addition, the selection also varies based on the different purposes of the study.

To demonstrate how this works, below is a sample dataset (Figure 1) created with five columns and ten rows. After dataset standardization (because columns may be collected in different scales), the heat map is applied.

heat map example 1

heat map example 2

In figure 2, columns and rows are re-arranged by similarity. The function used to compute dissimilarity between both rows and columns is the Euclidean Distance Method [1]. This could also be Maximum, Manhattan, Canberra, Minkowski Method or customized depending on the type of dataset (binary, continuous, or discrete etc.) and the purpose of study. For clustering columns/rows, along with the purpose of the study and correlation within and between subgroups, it is possible to form clustering in several possible numbers of groups (bigger than one and smaller than length of columns or rows).

The two figures below show an expansion of dendrograms on the top and left side of the heat map color body by applying cutoff lines to clustering. Once the groups are decided, a common way to further analyze is to choose one or, where appropriate, make a combination of all elements from each group to represent the entire group.

Heat Map example 2Heat Map example 4

Tip for Heat Maps

Where you see highly correlated variables (as often happens in regression models with a high number of variables), select variable with most interest from each group.  For example, early, middle and late onset insomnia and hypersomnia have been shown within a group (high similarity) by heat map.  If the study is interested in hypersomnia, then keep hypersomnia to represent the entire group; if it is interested in sleep pattern, summation of scores for all symptoms could be applied.


  2. Data Visualization with SAS/Graph, by Keith Cranford.
[1] Euclidean Distance Method: taking summation of squared differences between elements then taking square root.

Tags: programming, clinical programming, biostatistical information, Clinical BioStatistician, biostatistical analysis, Euclidean Distance Method, dendrogram, heat map, biostatistics, Pharmaceutical Data Analysis