Coherence is the essence of everything successful. Then we add integrity.

December 2016

Curious look into Observational Studies

28. december 2016 at 22:13 | Veronika Valdova, ARETE-ZOE |  Medicine & Pharmacy
Making sense of large data sets has always been a daunting task, and every tool that makes the life of an analyst easier is worth exploring. There are 45,000 observational studies on the ClinicalTrials.gov database. This is how trial version of IBM Watson visualizes the data available. The dataset was minimally processed to reflect priority information requirements, in this case insight into the most commonly used study designs over time.

Observational study is a clinical study in which participants identified as belonging to study groups are assessed for biomedical or health outcomes. Participants may receive diagnostic, therapeutic, or other types of interventions, but the investigator does not assign participants to specific interventions.


Observational Study Design is described by MODEL (cohort; case-control; case-only; case-crossover; ecologic, family-based and other) and TIME PERSPECTIVE.

Observational Study Model: primary strategy for subject identification and follow-up:
  • Cohort: group of individuals with common characteristics who are examined or traced over a given time period.
  • Case-control: group of individuals with specific characteristics compared to group(s) with different characteristics, but otherwise similar.
  • Case-only: single group of individuals with specific characteristics.
  • Case-crossover: characteristics of case immediately prior to disease onset compared to characteristics of same case at a prior time.
  • Ecologic or community studies: geographically defined populations compared on a variety of environmental and/or global measures not reducible to individual level characteristics.
  • Family-based: studies conducted among family members, such as genetic studies within families or twin studies and studies of family environment.
Time Perspective - temporal relationship of observation period to time of subject enrollment.
  • Prospective: look forward using periodic observations collected predominantly following subject enrollment.
  • Retrospective: look back using observations collected predominantly prior to subject selection and enrollment.
  • Cross-sectional: observations or measurements made at a single point in time, usually at subject enrollment.


Clarity on priority information requirements - as well as quality of data, is essential to get meaningful output from any analytical tool, no matter how useful and handy.

In a world driven by compliance, can patients' interests prevail?

20. december 2016 at 16:48 | Veronika Valdova, ARETE-ZOE
Everybody knows what PII is and how important it is to ALWAYS anonymize case reports before sharing them with any third parties. These legal obligations, however, are not always enough to prevent subsequent data linkage by a determined and motivated researcher. Imagine a hypothetical example, such as this case study everyone with an email account is already familiar with: how much effort it would take to find out the dude's true identity, knowing his occupation and employer, his sister's name, and nature of his injuries?


The total number of patient records lost to hackers, other types of IT incidents, and theft, is staggering. In 2015, personal identifiable information of 113,267,174 individuals was affected in total number of 268 incidents. Compliance-driven industry did not stop these incidents from occurring, and did little to increase overall resilience against malicious intrusions and tampering.



"Do not disturb my circles!"
The most famous case of a medical device purposefully altered to prevent targeted attack by terrorists is Dick Cheney's pacemaker. But there are many other examples of medical devices that are potentially life-threatening, from insulin pumps to patient life functions monitors.
Security Researchers have long warned that the IT security on medical devices is lacking and malware runs " rampant" in hospital environments. Often, medical software tends to be older and more vulnerable than consumer tech because updating the software might risk running afoul of their Food and Drug Administration approval. ( The Washington Post)

"Sit down and relax while I go there and wet the tea"

Patient records are private for a reason. It is not always the best idea to share medical records, wittingly or not, with representatives of different cultures. Their understanding of the patient's welfare may be entirely different.
The biggest problem with patient data leaks is that the party most affected by inappropriate handling of medical data is the patient, rather that the owner of the data. So whilst consequences of internal security failure may be financial in nature, as a result of failure to comply, for affected patients such incident can be life-threatening. How long it will take to start taking patient records and hospital data seriously?

Meditation over serialization in pharmaceutical supply chain and opportunities for pharmacovigilance and quality control

20. december 2016 at 16:32 | Veronika Valdova, ARETE-ZOE
New serialization legislation required for pharmaceutical products has the potential to transform how we think about pharmacovigilance and quality control, and help connect information relevant for these industry functions.

New serialization legislation, package-level identifiers and safety features

The Falsified Medicines Directive of 2011 introduces new harmonized, pan-European measures to ensure that medicines are safe and that the trade in medicines is rigorously controlled. These new measures include:

  • Obligatory safety features on the outer packaging of the medicines (Commission Delegated Regulation (EU) 2016/161)
  • A common, EU-wide logo to identify legal online pharmacies.
  • Tougher rules on the controls and inspections of producers of active pharmaceutical ingredients,
  • And strengthened record-keeping requirements for wholesale distributors.
In March 2010, the FDA issued recommendations in the Standard Numerical Identifier (SIN) Guidance explaining the FDA's current thinking on the structure, format, and content of uniquely labeled package-level identifiers. The guidance is intended to assist with the development of standards and systems for identification, validation, authentication, and tracking and tracing of prescription drugs at package level.
The Drug Quality and Security Act (DQSA), was signed into law by President Obama on November 27, 2013. Title II of DQSA, the Drug Supply Chain Security Act, outlines critical steps to build an electronic, inter-operable system to identify and trace certain prescription drugs as they are distributed in the United States. Ten years after enactment, the system will facilitate the exchange of information at the individual package level about where a drug has been in the supply chain.
Historically the U.S. Pharmacopeia has worked to ensure their standards and General Chapters complement regulatory documents such as the FDA Title 21 of the Code of Federal Regulation Part 211 on current Good Manufacturing Practices. USP 1083 covers all areas of sourcing and distribution of packaging materials, active pharmaceutical ingredients, excipients and final products, including clinical trial materials. The guideline applies to not only pharmaceuticals, but also medical devices, combination products, and dietary supplements.

So what is the impact of this new legislation on the way how we go about pharmacovigilance?

Traditional understanding of pharmacovigilance by the industry is that it is a purely compliance function. Main vulnerabilities are internal and external inter-dependencies stemming from organizational structure, outsourcing, reorganizations due to acquisitions and mergers, and (in)compatibility of systems used before and after change.
Threats include incompetence resulting from inability to appropriately train staff on pharmacovigilance as a result of ambiguity in process, human error caused by improvisation and inconsistent application of regulations, and inconsistent quality of information that meets the minimum reporting requirements but does not provide any other useful information.
In pharmacovigilance and clinical research context, adverse consequence typically means regulatory action for non-compliance (See MHRA inspections report for 2015-16 and EMA metrics).

But ... what if the Priority Information Requirements (PIR) change?

Minimum information requirements for ADR reporting include identifiable reporter, identifiable patient, drug involved, and event. This dataset satisfies regulators but provides no meaningful information to the Market Authorization Holder - except for satisfying compliance.
Safety reports are only as good as the information received. MAH may wish to know other attributes to be able to asses quality and make meaningful assessment of the eventProperly designed process that accounts for newly defined PIRs translates into SOPs and working instructions for own staff, vendors and service providers.
Information about the product such as history of storage conditions, batch numbers, or expiration date, can be included by simply scanning the product code in an electronic report. Accurate identification and other information relating to the drug allows the collector to distinguish between:

  • Adverse drug reactions
  • Quality issues, expired or improperly stored product
  • Suspected counterfeit drugs in legitimate supply chain
  • Diversion of legitimate products for illicit use
  • And products obtained through illicit channels
Additional information collected about the context of use of certain drugs may include diagnosis, off-label use, medication error, misuse/abuse, and overdose.
Inclusion of various quality indicators as re-defined in Priority Information Requirements in data collection would make data collection pharmacovigilance data operationally meaningful.

Why training makes all the difference - even in pharma

20. december 2016 at 16:26 | Veronika Valdova, ARETE-ZOE
The current operational environment in the pharmaceutical industry is the result of long-term trends: industry consolidation, globalization, and outsourcing.
Companies are growing in size due to acquisitions and mergers. Operations routinely span across geographical, jurisdictional and cultural boundaries. The trend of industry consolidation continues in 2015 and 2016: the total number of deals flattened and remained even at around 600 mergers a year. Geographically, mergers and acquisitions have been shifting from the U.S. to Western Europe. This shift is the result of transactions driven by the need to add complementary products to the core business areas, and tax inversions.
Pharmaceutical industry outsourcing in manufacturing, specialized services, clinical research, and even pharmacovigilance, has grown during the past 10 years and this trend is likely to continue. Outsourcing includes full range of corporate activities-from screening and lead identification, to toxicology and other pre-clinical studies, clinical trials, marketing, and manufacturing at all scales. The main outsourcing areas include product characterization testing, validation services, toxicity testing, analytical testing, and fill-finish operations. Much of the growth in outsourcing in the past decade has taken place in China and India.
The result of industry trends is increasing risk of disruptions due to reorganizations, complex vendor relationships, cultural and legal differences, single-source supply chain, high-impact accidents, natural disasters and other factors.
Pharmaceutical industry is global, complex, international, and highly regulated. Training is one of the most important ways, how to decrease internal vulnerabilities and improve organizational resilience.
To accommodate constantly changing needs, adapt to changing operational environment, and to achieve greater resiliency and agility, organizations need to be able to train their existing and newly coming workforce in much more systematic and flexible manner.

Regulatory environment in pharmaceuticals is constantly changing. Often conflicting national and international requirements and policies have to be translated into organizational SOPs and working instructions in a way that ensures unambiguous interpretation. This process requires coordinated inter-departmental effort to ensure consistency in implementation, to reduce liability stemming from non-compliance caused by lack of competency, need for improvisation, differences in interpretation, and human error.
Complexity of organization affects the number of entities involved in handling material and information, and increases the complexity of operations concerning its internal and external relations, roles and responsibilities and tasks assigned to functions, access rights management, and ultimately training requirements.
Globalization affects all functions of any enterprise from financial and legal to security situation in regions of interest. Increasing distance and time zone differences make the system slower to respond in case of disruptions. Training improves individual and collective ability to solve operational challenges aggravated by cultural diversity, differing communication styles, language barrier, and other factors in standard situations, as well as during crises.
Increasing complexity of operations is the result of changing nature of products traded. Consolidation of the industry increases complexity of organizations and their internal and external relationships, and limits sourcing options. Shift from blockbuster medicines to orphan medicines, individualized treatments and niche products increases the costs of operations. High volume products with predictable demand are managed differently and often follow different supply and distributions models than products with low and unpredictable demand.
Information management systems become more sophisticated and complex in response to these trends. New technologies, although valuable, create new vulnerabilities for the enterprise. Human ability to recognize and deter new threats is essential to counter social engineering efforts, hacking and data breaches.
After all, highly trained and qualified people are the most valuable assets of every learning organization.


Ray of Light: Access to clinical trial data

20. december 2016 at 16:24 | Veronika Valdova, ARETE-ZOE


The clinical data publication website was developed to implement EMA Policy 0070, and is maintained by the EMA communications department.



The policy covers clinical data, both clinical reports and individual patient data, submitted under the centralized marketing authorization procedure after 01-Jan-2015, and extension of indication / line extension applications submitted after 01-Jul-2015, or as part of a procedure under Article 58 of Regulation (EC) No 726/2004, or data submitted by a third party in the context of a Market Authorization Application (MAA) or post-authorization procedure, or as additional clinical data for scientific assessment.
There are two categories of access to the published clinical data:

The terms of use by definition exclude all commercial research as well as investors and sponsors who could use the data to analyze available evidence and to assess performance and value of new therapies under development and compare them to the current standard of care. Since many insurers and payers are commercial entities as well this resource is not available to them either. Many hospitals and research centers are public-private partnerships, would they count as non-commercial entities? The terms of use also exclude consultants who could use the resource to analyze and benchmark their clients' data.
Clinical reports include the following types of documents:
  • Clinical overview: a critical analysis of the clinical data submitted in the dossier, that presents the risks and limitations of the study, the study results, analysis of benefits and risks of the medicinal product, and description how the study results support the prescribing information;
  • Clinical summary: a detailed factual summary of the clinical information, including information provided in clinical study reports from any meta-analyses or other cross study analyses, as well as post-marketing data for products that have been marketed outside of the EU;
  • Clinical study report: a detailed scientific document about the methods and results of a clinical trial addressing safety and efficacy. Protocol and protocol amendments describe the objectives, design, methodology, statistical considerations and organization of a clinical trial. Sample case report form is a questionnaire used by the trial sponsor to collect data from each participating site. Finally, documentation of statistical methods provides a description of the planned methods for collection, analysis, interpretation, presentation, and organization of the data.
The AllTrials initiative has been asking very legitimate questions about trials that are never published and never presented to the professional public.
The first version of ClinicalTrials.gov was made available to the public on February 29, 2000. In September 2005, the International Committee of Medical Journal Editors began requiring trial registration as a condition of publication Two years later, in December 2007, the expanded registration requirements of FDAAA began and were implemented. Both events substantially increased the numbers of registered trials.
Out of 228,575 trials on the database, 52% have been completed (see definitions)
Out of the 118, 981 completed studies registered in ClinicalTrials.gov, only 16% have posted results. The remaining 84% do not. Out of 110,565 trials completed more than a year ago, only 19,246 have results available to the public. Section 801 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) requires the submission of "basic results" for certain clinical trials, generally no later than 1 year after their Completion Date.
Under section 402(j) of the PHS Act, sponsors of certain clinical trials of FDA-regulated products have been required to register them at ClinicalTrials.gov since December 26, 2007. Summary results information for clinical trials of approved products has to be submitted as of September 27, 2008, and certain adverse events information since September 27, 2009.
This final rule clarifies which clinical trials of FDA-regulated products must be submitted to ClinicalTrials.gov. The final rule also describes an approach for evaluating, prior to registration, whether a particular clinical trial or study is an applicable clinical trial (see Section IV.A.5 and Section IV.B.2).

So it seems that results from clinical trials are slowly but surely becoming publicly available for public scrutiny. The next issue to solve will be standardization of results to make them comparable.
CONSORT 2010 Standardization of reporting of clinical trials is essential for their review and assessment. CONSORT 2010, as developed by the CONSORT group, contains a 25-item checklist and flow diagram. Extensions of the CONSORT Statement have been developed for different types of trial designs, different interventions, and different types of data.
COS-STAR
An international group that included experienced COS developers, methodologists, journal editors, potential users such as clinical trialists, systematic reviewers, and clinical guideline developers, as well as patient representatives developed the Core Outcome Set-STAndards for Reporting (COS-STAR) Statement as a reporting guideline for COS studies.
On October 18, the group published their work in PLOS Medicine: "Core Outcome Set-STAndards for Reporting: The COS-STAR Statement". The COS-STAR Statement consists of a checklist of 18 items considered essential for transparent and complete reporting in all COS studies:

The value of curiosity

20. december 2016 at 16:13 | Veronika Valdova, ARETE-ZOE
On October12, Merck KGAA (Darmstadt) published a very interesting study that appears to address lagging performance in innovation in the industry by including personal characteristics in hiring decisions. The company scrutinizes its new hires for curiosity.
Merck Publishes First International Curiosity Study Merck examined with its Curiosity Study 2016 the extent to which staff are able to make the most of their curiosity at work, and if they are encouraged to do so.
"73% of respondents do not feel comfortable asking more questions at work. Nearly 45% workers surveyed in Germany believe that they are discouraged by their employer from challenging the status quo. 35 % of German employees cited self-directed work as the most important factor. "
Pharmaceutical innovation has been suffering from problematic performance for years. And the core problems are largely organizational and cultural. Bruce Booth in his article "Culture as a culprit of the Pharma R&D crisis?" (Forbes, 2012), highlights factors such as "tyranny of the committee", "stagnation through risk avoidance", and "negative impact of organizational entropy". The article stirred a debate in the industry about cultural factors that affect human behavior within the system, namely willingness of individuals to present new ideas that may or may not succeed. Instead, natural human preference is "playing it safe" and stick with projects that have approved budgets to avoid layoffs during acquisitions and mergers.
In 2012, Derek Lowe in his article Eroom's Law (In the Pipeline, 2012) commented on long-term trend in cost of developing a new drug:
"Now, the companies (and CEOS) involved in this generally talk about how they're going to turn things around, how cutting their own research will put things on a better footing, how doing external deals will more than make up for it, and so on. But it's getting increasingly hard to believe that."

Richard Wobbe, in discussion below the article, posted a link to his article Project Management and Drug Discovery Productivity (page 8, figure 3) in which he presents the same problem in a differently designed graph (1960-1998), showing the same problem from a different angle. Combined graph showing R&D spending and number of approved drugs/year:
The Big Pharma culture has been homogenised, purified, sterilised, whipped, stirred, filtered, etc. and lost its ability to ferment the good stuff required to innovate. This isn't covered in most reviews of the productivity challenge facing our industry, because it's nearly impossible to quantify, but it's well known and a huge issue". ' From Vision to Decision Pharma 2020'
Sayle in his article Creating a Culture of Trust & Breakthrough Innovation in Pharma (EyeForPharma, 2015) dissected several analytical works such as PWC's Report 'From Vision to Decision Pharma 2020' and 'The Corporate Reputation of Pharma - The Patient Perspective' and discussed the role of culture in pharmaceutical innovation. Sayle highlights the role of trust:
"So what can the industry's senior figures do to rebuild public trust and build healthy, high-performing companies to successfully meet pharma's fundamental challenges of the future?"
I wholeheartedly agree: public trust is essential for the industry to thrive. Without trust, no business is possible. Loss of public trust has the power to force major industry reform, such as the changes implemented in nuclear industry following the Three Mile Island accident. In extreme circumstances, as seen after the Chernobyl disaster in Soviet Union in 1986, failure to reform can trigger a regime change. For dynamic version of the presentation see Arete-Zoe company website or SlidePlayer.
In pharma, nothing goes away unless it's well and truly superseded - some of the oldest drugs such as ibuprofen and aspirin, metformin, cholesterol-lowering drugs, and anti-hypertensives still sell worldwide, many are on the WHO list of essential medicines, and their cost is generally very low. In fact, many essential drugs do go away as a result of business decisions: to create room for drugs that are newer and where it is possible to charge premium price.
Recently a new trend emerged to offer half-a-century old drugs for a premium price: Innovators vs. exploiters (Forbes, 2016) comment on Mylan's EpiPen, Citron's last word on Valeant's business model, or the price hike of daraprim by Turing Pharmaceuticals, just to name a few. See House Hearing on drug pricing

So why is drug development becoming so expensive, then?

Series of mergers and mega-mergers in the industry significantly affects the drug development pipeline, and the culture within which people, including scientists, operate. Recent research published by HRB (August 2016) shows that mergers do indeed stall innovation:
"Acquirers often target firms that have a relatively similar patent portfolio. That means there's less competition for discovering and developing new therapies. If a non-merging rival is also researching similar therapies, that outside firm also now has one less competitor. It experiences a similar reduction in competition as the acquiring firm."
With all due respect, this practice closely resembles behavior of sand tiger shark embryos in the womb: they cannibalize each other. As pointed out by FiercePharma, McKinsey & Co. analysts in their 2014 report emphasized the "shareholder value" effects of megamergers.

The value of curiosity

The role of organizational culture in pharmaceutical innovation is hard to overestimate. No man is an island: People function within an organization, not independently of it, thoroughly immersed in its culture, having to respect its reporting structure, encouraged (and more often than not discouraged) to undergo training that is relevant to their (current) job, with endorsed (or not) excursions into other areas of interest. Promotion issues and career ladder, mobility within the enterprise, and choices presented to internal talent all affect whether or not people communicate their preferences, develop the talents they have, and pursue their dreams.