By Christopher Hurley, MBA, Manager, Clinical Programming & Biostatistics
The Theory of Constraints (TOC) is a unique management philosophy that strives for a rationale or scientific approach to management. It provides a way to simplify the complexity of human-based systems and still keep the main issues and impacts under managerial control.
- TOC was initially developed for manufacturing but can be used in any industry
- Compatible with Six-Sigma, Lean and other methodologies
- Provides methodology to develop our own common sense solutions, based on our own circumstances and understanding, not something “canned”
- Every organization has a goal to achieve. In clinical programming, our goal is to maximize our ability to fulfill requirements
- An organization is more than the sum of its parts. Achievement of goal depends on synchronization of parts or people in a combined effort
- The performance of an organization is constrained by very few variables. Every part or person producing at 100% all of the time is impossible because of interdependencies and timing
Physical Constraints – such as hours in a day, network bandwidth, and licenses
Policy and Paradigm Constraints – such as system access, SOPs, and archaic rules
There are Five Focusing Steps to Break Constraints
Step 1 - Identify the system’s constraint(s)
What don’t we have enough of? Is there any part of the organization that is waiting for something? Is the constraint where it should be?
Step 2 - Decide how to exploit the systems constraints
How do we get the most with what we’ve got? What does the part of the organization do that others can do? If the constraint can be immediately removed without large investments, do it now and go back to Step 1.
Step 3 - Subordinate everything else to the decisions made in Step 1 and 2.
Make sure everyone in the organization is aligned with exploitation decisions
Step 4 – Elevate the system’s constraints
Evaluate alternatives and then execute the way you have chosen to elevate the constraints
Step 5 – Don’t allow inertia to be the system’s constraint
The constraint may have moved. Go back to Step 1 and find it.
Analyses of Change
Every improvement is a change but not every change is an improvement. TOC analysis enables us to develop solutions to the right problems using the following types of analyses.
- What to change? Current Reality Tree Analysis
- To what to change? Future Reality Tree Analysis
- How to cause the change? Transition Tree Analysis
- Cause and effect logic is used in each analysis. Each of the aforementioned trees looks like a flowchart showing all of the consequences from each condition or action.
- Each analysis is a blend of common sense, intuition and purposeful action
At MMS we have implemented TOC analyses to determine root causes for various issues and then developed solutions to resolve those issues. TOC is an excellent methodology to employ for quickly developing solutions to the right problems. TOC allows us to develop well thought out plans and initiatives to overcome the obstacles standing in the way of our goals and objectives.
How has the Theory of Constraints affected your workplace?
"The Theory of Constraints Way to Overcome Resistance to Change,"- Low, J. Proceedings of the American Production and Inventory Control Society (APICS) International Conference and Exposition, Las Vegas, October 6-9, 2003.
By Diganta Bose, BE, MS, Clinical Programmer
The completion of the Human Genome Project (2003) and Bioinformatics research has created an opportunity for a significant rise in a new breed of data in both research and clinical care. This new kind of data, generated as a result of Pharmacogenomics (PGx) research, promises understanding of molecular pathways and underlying disease risks in populations at a more appropriate, quantitative and qualitative way.
The PGx team, a sub-team within the CDISC SDS Team (Clinical Data Interchange Standards Consortium-Study Data Submission), has developed several domains designed to carry Pharmacogenomics data. The development of these CDISC PGx domains was done in parallel with the work being done by the HL7 (Health Level Seven, an authority that sets standards in Information Technology for Healthcare Research) Clinical Genomics Work Group (CG), which was initiated jointly several years ago by CDISC and HL7. This creates new opportunities and challenges for the SAS programmers working on CDISC complaint data structures.
Pharmacogenomics - the science and the data
Pharmacogenomics (PGx) is a branch of pharmacology which explains the relationship between genetic variations and drug response in patients by correlating gene expression or SNPs (Single Nucleotide Polymorphism) with a drug’s efficacy and toxicity. Such studies can help to develop rational means to optimize drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects. Such approaches promise the advent of "personalized medicine"; in which drugs and drug combinations are optimized for each individual's unique genetic makeup.
Pharmacogenomics information is helpful particularly when it comes to cancer trials; pharmacogenomics tests are used to identify which patient will have toxicity from commonly used cancer drugs and identify which patient will not respond to commonly used cancer drug. The tests most commonly include gene expression analysis using microarrays, which can be performed on specific tissues specimens collected from the patients. Other tests may include SNP or any genetic polymorphism analysis, genotyping and a few more. The data one would expect out of such PGx tests are mainly biospecimen and genetic (DNA, RNA) samples along with their date and time captures including clinical significance information.
Handling, manipulating and analyzing the data - A SAS Programmer’s challenge
The PGx Findings domain stores key results such as intensity values (both raw and normalized), P-Value, fold-change, ratio, genetic change, amino-acid change, etc. Such data are significantly different from the currently available findings module (Lab data, Vital Signs, Pharmacokinetic data, etc.).
The HL7 CG has developed a Genetic Variation model in conjunction with clinical care participants such as Partners Healthcare and Intermountain Healthcare who are leading the adoption of PGx in healthcare. As part of the HL7 work, LOINC (Logical Observation Identifiers Names and Codes) was extended to include the most commonly used genetic variation tests. CDISC plans to create vocabulary for CDISC TESTCD and TEST which will reside in the NCI EVS (National Cancer Institute’s Enterprise Vocabulary Services) and be a counterpart to the LOINC codes. The NCI is currently working with the group that originally developed the Microarray and Gene Expression (MGED) standards, to validate and populate the Ontologies for Biomedical Investigators (OBI) into EVS. This ontology will be used for the Gene Expression data by both CDISC and HL7.
The initial package contains the following domains: BS-Biospecimen, BE-Biospecimen Event, ES-Extracted sample, PG-Pharmacogenomics, PF-Pharmacogenomics Findings.
A genetic variation data could be anything from complex arrangements of strings that looks like random character strings (generally A T G (U) C in case of a DNA/RNA sequence information like a gene substring) to strings or number arranged in an ambiguous array which actually holds some hidden meaning that need to be decoded again by some complex algorithm which a programmer has to implement. Unlike the other finding variables, which contains derived or assigned values that are simple to understand letters or text, numeric values and discrete values (Yes/No, 0/1, Male/Female), the variables in the PGx domain may not be necessarily simple and a programmer may need to think of rules and very specific programming to derive certain variables from the captured raw data in order to make them CDISC data structure complaint. Programming may involve developing macros to automate standardized algorithms across the domains and major operations effective to handle complex strings such as using regular expressions and string functions. Mapping codes likely will involve databases like NCBI (National Center for Biotechnology Information) and GenBank along with medical dictionaries like MeddRA and WHODRUG. All these new kind of data collected in PGx domains brings new opportunities for more flexible SDTM (Study Data Tabulation Model) and ADaM (Analysis Data Model) programming for CDISC.
For details read the CDISC Pharmacogenomics news article available on the CDISC website at http://www.cdisc.org/pgx-review-article
By Dr. Arunima Sen, MD, PDCR, ACCR, Sr. Manager, Pharmacovigilance & Medical Affairs
The French playwright Moliere, some hundred years ago had said “to undergo treatment you have to be very healthy, because apart from your sickness you have to withstand the medicine”. It is an undeniable fact even today that, adverse drug reactions (ADR) are the cause for many hospitalizations, significant morbidity and sometimes even death. This is also the basic premise which led to the development of Pharmacovigilance as a science that ultimately aims to prevent adverse drugs reactions and its impact on patients, both in premarketing and post marketing phases of drug development.
The foundation stone for Pharmacovigilance was laid in the 1960s with the launch of WHO’s Program for International Drug Monitoring in 1968. From that time onwards WHO’s relentless work and the rigorous legislations and guidelines by the regulatory agencies of most of the countries have shaped Pharmacovigilance as a domain that has extended beyond the strict confines of detecting new signals of safety concerns and has become a tool for development and marketing of safer medicines.
It is interesting to note some of the evolving country specific legislations and guidelines that has helped shape Pharmacovigilance as it is seen today.
Some important US Legislation by FDA which paved the way of proactive Pharmacovigilance:
FDAAA (FDA Amendments Act)
- Passed in 2007 and effective in 2008, this was the most comprehensive revision bringing sweeping safety reform. Title XI of FDAAA demands REMS (Risk Evaluation and Mitigation Strategy) for identified drugs and also imposes stricter post marketing safety surveillance from marketing authorization holders (MAH).
Some newer FDA Initiatives to enhance the safety of drugs in the developmental stage are:
- Enhanced developmental safety assessment, e.g.- generating industry guidance document for premarketing safety assessment for drug induced liver injury (DILI)
- Safe Use Initiative, 2009: a program aimed at reducing the likelihood of preventable harm from medication use. By this program the FDA aims to collaborate with health care professionals and other stakeholders to identify drugs that are linked to preventable harm and devising mechanism to overcome them.
- IND regulation revision Sep 2010 : On 29 September 2010, FDA released the final ruling and draft guidance for amending Regulation 21 CFR Parts 312 and 320 governing safety reporting requirements for INDs and bioavailability (BA)/ bioequivalent (BE) studies. The new requirements are designed to (i) improve the overall usefulness and quality of safety reporting and the agency’s ability to review critical information, (ii) strengthen FDA’s ability to review critical safety information, (iii) improve safety monitoring of human drug and biological products and (iv) harmonize safety reporting with recommendations made by ICH, CIOMS and EU.
Some EU Legislation that helped the development of Pharmacovigilance
- ‘Risk Management Plan’ was introduced in 2005 as an EU initiative to ensure that the benefits of a particular medicine exceed the risks
- EU Directive 2010/84: (published on 15 December 2010 and will become effective from 21 July 2012) enforces EU coordination of PV activities via coordination group / PV Risk Assessment Committee. Some of the other important areas that this directive talks about is:
- Direct reporting of SAR (suspected adverse reactions)by HCPs and patients
- MAH reporting only suspected adverse reactions (clarification of AE vs. ADR)
- Improved SmPC (Summary of Product Charateristics)of a drug
Some other newer EU initiatives in drug safety:
- ENCePP: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. This initiative aims to enhance post authorization monitoring of medicinal products by multicentre safety / lack of efficacy studies.
- EU Innovative Medicines Initiative –IMI. This program looks in to Stakeholder collaboration to accelerate development of effective medicines with fewer adverse effects by
- Improved predictivity of safety
- Improved predictivity of efficacy
- Knowledge management
- Education and Training
Newer Pharmacovigilance initiatives in India
Pharmacovigilance Program of India (PVPI) was launched in July 2010 with the goals of monitoring ADRs in Indian population, to create awareness amongst health care professionals, to monitor benefit-risk profile of medicines in India, generate evidence based recommendations and advise CDSCO (Central Drugs Standard Control Organization) for safety related regulatory decisions for medicines. This program is directly under the ministry of health and family welfare and ADR monitoring centers being set up in 40 medical colleges across India.
In conclusion, it can be said that from the time of the ignominious thalidomide tragedy in late 1950s to the more recent rofecoxib and rosiglitazone controversy, the science of Pharmacovigilance has come a long way. From the very “reactive” nature of Pharmacovigilance, which looked in to drug safety as just a mere regulatory requirement on part of the marketing authorization holder to a stage where it proactively can generate safety signals and help get safer drugs to the market, the international landscape of Pharmacovigilance has changed considerably. Right now, Pharmacovigilance is poised to overcome many hurdles in its path to become one of the most important bridges between the patient, the healthcare professionals and the pharmaceutical companies for a safer health care.
MMS Holdings Inc. today announced a financial gift to aid the relief efforts in the areas of Japan affected by the March 11, 2011 devastating 9.0 magnitude earthquake and tsunami. There are thousands of individuals in need in Japan and MMS is one of the many organizations that have stepped up to lend a hand.
MMS Holdings funds will go to the American Red Cross that will use this contribution towards the much-needed healthcare services and medical supply needs of the local victims in Japan.
“Our thoughts go out to our colleagues and friends in Japan along with their families” said MMS Vice President, Prasad Koppolu. “We as an organization hope that our support of the American Red Cross greatly helps a number of Japanese people as well as those involved in the recovery efforts.”
MMS Holdings is a niche pharmaceutical service organization currently partnering with and has long-standing relationships with a number of Japan-based pharmaceutical companies. MMS colleagues hope for the quickest possible recovery for those affected communities.
About MMS Holdings Inc.
MMS Holdings Inc. is based in Canton, MI and is a highly experienced pharmaceutical service organization that is focused on quality deliverables in the areas of Clinical Programming, Biostatistics, Medical /Regulatory Writing and Comprehensive Pharmacovigilance. Commitment to Quality deliverables with robust submission experience sets MMS apart from traditional service providers. MMS Holdings Inc. is ISO-9001 certified for all services and maintains detailed quality metrics for every project. For more information visit: http://www.mmsholdings.com