Posts Tagged ‘Regulatory’

#TUBiol5227: Biomarkers & Biotargets: Genetic Testing and Bioethics

Curator: Stephen J. Williams, Ph.D.

The advent of direct to consumer (DTC) genetic testing and the resultant rapid increase in its popularity as well as companies offering such services has created some urgent and unique bioethical challenges surrounding this niche in the marketplace. At first, most DTC companies like 23andMe and Ancestry.com offered non-clinical or non-FDA approved genetic testing as a way for consumers to draw casual inferences from their DNA sequence and existence of known genes that are linked to disease risk, or to get a glimpse of their familial background. However, many issues arose, including legal, privacy, medical, and bioethical issues. Below are some articles which will explain and discuss many of these problems associated with the DTC genetic testing market as well as some alternatives which may exist.

‘Direct-to-Consumer (DTC) Genetic Testing Market to hit USD 2.5 Bn by 2024’ by Global Market Insights

This post has the following link to the market analysis of the DTC market (https://www.gminsights.com/pressrelease/direct-to-consumer-dtc-genetic-testing-market). Below is the highlights of the report.

As you can see,this market segment appears to want to expand into the nutritional consulting business as well as targeted biomarkers for specific diseases.

Rising incidence of genetic disorders across the globe will augment the market growth

Increasing prevalence of genetic disorders will propel the demand for direct-to-consumer genetic testing and will augment industry growth over the projected timeline. Increasing cases of genetic diseases such as breast cancer, achondroplasia, colorectal cancer and other diseases have elevated the need for cost-effective and efficient genetic testing avenues in the healthcare market.

For instance, according to the World Cancer Research Fund (WCRF), in 2018, over 2 million new cases of cancer were diagnosed across the globe. Also, breast cancer is stated as the second most commonly occurring cancer. Availability of superior quality and advanced direct-to-consumer genetic testing has drastically reduced the mortality rates in people suffering from cancer by providing vigilant surveillance data even before the onset of the disease. Hence, the aforementioned factors will propel the direct-to-consumer genetic testing market overt the forecast timeline.

DTC Genetic Testing Market By Technology

Get more details on this report – Request Free Sample PDF

Nutrigenomic Testing will provide robust market growth

The nutrigenomic testing segment was valued over USD 220 million market value in 2019 and its market will witness a tremendous growth over 2020-2028. The growth of the market segment is attributed to increasing research activities related to nutritional aspects. Moreover, obesity is another major factor that will boost the demand for direct-to-consumer genetic testing market.

Nutrigenomics testing enables professionals to recommend nutritional guidance and personalized diet to obese people and help them to keep their weight under control while maintaining a healthy lifestyle. Hence, above mentioned factors are anticipated to augment the demand and adoption rate of direct-to-consumer genetic testing through 2028.

Browse key industry insights spread across 161 pages with 126 market data tables & 10 figures & charts from the report, “Direct-To-Consumer Genetic Testing Market Size By Test Type (Carrier Testing, Predictive Testing, Ancestry & Relationship Testing, Nutrigenomics Testing), By Distribution Channel (Online Platforms, Over-the-Counter), By Technology (Targeted Analysis, Single Nucleotide Polymorphism (SNP) Chips, Whole Genome Sequencing (WGS)), Industry Analysis Report, Regional Outlook, Application Potential, Price Trends, Competitive Market Share & Forecast, 2020 – 2028” in detail along with the table of contents:

Targeted analysis techniques will drive the market growth over the foreseeable future

Based on technology, the DTC genetic testing market is segmented into whole genome sequencing (WGS), targeted analysis, and single nucleotide polymorphism (SNP) chips. The targeted analysis market segment is projected to witness around 12% CAGR over the forecast period. The segmental growth is attributed to the recent advancements in genetic testing methods that has revolutionized the detection and characterization of genetic codes.

Targeted analysis is mainly utilized to determine any defects in genes that are responsible for a disorder or a disease. Also, growing demand for personalized medicine amongst the population suffering from genetic diseases will boost the demand for targeted analysis technology. As the technology is relatively cheaper, it is highly preferred method used in direct-to-consumer genetic testing procedures. These advantages of targeted analysis are expected to enhance the market growth over the foreseeable future.

Over-the-counter segment will experience a notable growth over the forecast period

The over-the-counter distribution channel is projected to witness around 11% CAGR through 2028. The segmental growth is attributed to the ease in purchasing a test kit for the consumers living in rural areas of developing countries. Consumers prefer over-the-counter distribution channel as they are directly examined by regulatory agencies making it safer to use, thereby driving the market growth over the forecast timeline.

Favorable regulations provide lucrative growth opportunities for direct-to-consumer genetic testing

Europe direct-to-consumer genetic testing market held around 26% share in 2019 and was valued at around USD 290 million. The regional growth is due to elevated government spending on healthcare to provide easy access to genetic testing avenues. Furthermore, European regulatory bodies are working on improving the regulations set on the direct-to-consumer genetic testing methods. Hence, the above-mentioned factors will play significant role in the market growth.

Focus of market players on introducing innovative direct-to-consumer genetic testing devices will offer several growth opportunities

Few of the eminent players operating in direct-to-consumer genetic testing market share include Ancestry, Color Genomics, Living DNA, Mapmygenome, Easy DNA, FamilytreeDNA (Gene By Gene), Full Genome Corporation, Helix OpCo LLC, Identigene, Karmagenes, MyHeritage, Pathway genomics, Genesis Healthcare, and 23andMe. These market players have undertaken various business strategies to enhance their financial stability and help them evolve as leading companies in the direct-to-consumer genetic testing industry.

For example, in November 2018, Helix launched a new genetic testing product, DNA discovery kit, that allows customer to delve into their ancestry. This development expanded the firm’s product portfolio, thereby propelling industry growth in the market.

The following posts discuss bioethical issues related to genetic testing and personalized medicine from a clinicians and scientisit’s perspective

Question: Each of these articles discusses certain bioethical issues although focuses on personalized medicine and treatment. Given your understanding of the robust process involved in validating clinical biomarkers and the current state of the DTC market, how could DTC testing results misinform patients and create mistrust in the physician-patient relationship?

Personalized Medicine, Omics, and Health Disparities in Cancer:  Can Personalized Medicine Help Reduce the Disparity Problem?

Diversity and Health Disparity Issues Need to be Addressed for GWAS and Precision Medicine Studies

Genomics & Ethics: DNA Fragments are Products of Nature or Patentable Genes?

The following posts discuss the bioethical concerns of genetic testing from a patient’s perspective:

Ethics Behind Genetic Testing in Breast Cancer: A Webinar by Laura Carfang of survivingbreastcancer.org

Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk

23andMe Product can be obtained for Free from a new app called Genes for Good: UMich’s Facebook-based Genomics Project

Question: If you are developing a targeted treatment with a companion diagnostic, what bioethical concerns would you address during the drug development process to ensure fair, equitable and ethical treatment of all patients, in trials as well as post market?

Articles on Genetic Testing, Companion Diagnostics and Regulatory Mechanisms

Centers for Medicare & Medicaid Services announced that the federal healthcare program will cover the costs of cancer gene tests that have been approved by the Food and Drug Administration

Real Time Coverage @BIOConvention #BIO2019: Genome Editing and Regulatory Harmonization: Progress and Challenges

New York Times vs. Personalized Medicine? PMC President: Times’ Critique of Streamlined Regulatory Approval for Personalized Treatments ‘Ignores Promising Implications’ of Field

Live Conference Coverage @Medcitynews Converge 2018 Philadelphia: Early Diagnosis Through Predictive Biomarkers, NonInvasive Testing

Protecting Your Biotech IP and Market Strategy: Notes from Life Sciences Collaborative 2015 Meeting

Question: What type of regulatory concerns should one have during the drug development process in regards to use of biomarker testing? From the last article on Protecting Your IP how important is it, as a drug developer, to involve all payers during the drug development process?

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NCCN Shares Latest Expert Recommendations for Prostate Cancer in Spanish and Portuguese

Reporter: Stephen J. Williams, Ph.D.

Currently many biomedical texts and US government agency guidelines are only offered in English or only offered in different languages upon request. However Spanish is spoken in a majority of countries worldwide and medical text in that language would serve as an under-served need. In addition, Portuguese is the main language in the largest country in South America, Brazil.

The LPBI Group and others have noticed this need for medical translation to other languages. Currently LPBI Group is translating their medical e-book offerings into Spanish (for more details see https://pharmaceuticalintelligence.com/vision/)

Below is an article on The National Comprehensive Cancer Network’s decision to offer their cancer treatment guidelines in Spanish and Portuguese.

Source: https://www.nccn.org/home/news/newsdetails?NewsId=2871

PLYMOUTH MEETING, PA [8 September, 2021] — The National Comprehensive Cancer Network® (NCCN®)—a nonprofit alliance of leading cancer centers in the United States—announces recently-updated versions of evidence- and expert consensus-based guidelines for treating prostate cancer, translated into Spanish and Portuguese. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) feature frequently updated cancer treatment recommendations from multidisciplinary panels of experts across NCCN Member Institutions. Independent studies have repeatedly found that following these recommendations correlates with better outcomes and longer survival.

“Everyone with prostate cancer should have access to care that is based on current and reliable evidence,” said Robert W. Carlson, MD, Chief Executive Officer, NCCN. “These updated translations—along with all of our other translated and adapted resources—help us to define and advance high-quality, high-value, patient-centered cancer care globally, so patients everywhere can live better lives.”

Prostate cancer is the second most commonly occurring cancer in men, impacting more than a million people worldwide every year.[1] In 2020, the NCCN Guidelines® for Prostate Cancer were downloaded more than 200,000 times by people outside of the United States. Approximately 47 percent of registered users for NCCN.org are located outside the U.S., with Brazil, Spain, and Mexico among the top ten countries represented.

“NCCN Guidelines are incredibly helpful resources in the work we do to ensure cancer care across Latin America meets the highest standards,” said Diogo Bastos, MD, and Andrey Soares, MD, Chair and Scientific Director of the Genitourinary Group of The Latin American Cooperative Oncology Group (LACOG). The organization has worked with NCCN in the past to develop Latin American editions of the NCCN Guidelines for Breast Cancer, Colon Cancer, Non-Small Cell Lung Cancer, Prostate Cancer, Multiple Myeloma, and Rectal Cancer, and co-hosted a webinar on “Management of Prostate Cancer for Latin America” earlier this year. “We appreciate all of NCCN’s efforts to make sure these gold-standard recommendations are accessible to non-English speakers and applicable for varying circumstances.”

NCCN also publishes NCCN Guidelines for Patients®, containing the same treatment information in non-medical terms, intended for patients and caregivers. The NCCN Guidelines for Patients: Prostate Cancer were found to be among the most trustworthy sources of information online according to a recent international study. These patient guidelines have been divided into two books, covering early and advanced prostate cancer; both have been translated into Spanish and Portuguese as well.

NCCN collaborates with organizations across the globe on resources based on the NCCN Guidelines that account for local accessibility, consideration of metabolic differences in populations, and regional regulatory variation. They can be downloaded free-of-charge for non-commercial use at NCCN.org/global or via the Virtual Library of NCCN Guidelines App. Learn more and join the conversation with the hashtag #NCCNGlobal.

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, in press. The online GLOBOCAN 2018 database is accessible at http://gco.iarc.fr/, as part of IARC’s Global Cancer Observatory.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network® (NCCN®) is a not-for-profit alliance of leading cancer centers devoted to patient care, research, and education. NCCN is dedicated to improving and facilitating quality, effective, efficient, and accessible cancer care so patients can live better lives. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) provide transparent, evidence-based, expert consensus recommendations for cancer treatment, prevention, and supportive services; they are the recognized standard for clinical direction and policy in cancer management and the most thorough and frequently-updated clinical practice guidelines available in any area of medicine. The NCCN Guidelines for Patients® provide expert cancer treatment information to inform and empower patients and caregivers, through support from the NCCN Foundation®. NCCN also advances continuing educationglobal initiativespolicy, and research collaboration and publication in oncology. Visit NCCN.org for more information and follow NCCN on Facebook @NCCNorg, Instagram @NCCNorg, and Twitter @NCCN.

Please see LPBI Group’s efforts in medical text translation and Natural Language Processing of Medical Text at

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“Repurposing” Off-patent Drugs offers big hopes of New Treatments

Reporter: Irina Robu, PhD

Given the substantial costs and the slow pace of drug discovery and development, repurposing old drugs has become a practice, partly because it involves the use of already developed compounds. Yet, there is lack of clinical interest in repurposing off patent drugs.

However, the scale of the opportunity for drug repurposing is huge. Initially approved for one disease, these drugs went off-patent and now show potential in other diseases. Even so, many non-profit groups see promise in supporting trials into drug repurposing. There is a huge untapped medicine chest of generic drugs with unexploited uses. These generic drugs are often cheap, already approved, off-patent and relatively quick to develop, whereas new drugs can cost millions of dollars to develop, test and 45% of the drugs fail in clinical trials.

However, numerous non-profit groups see potential in supporting trials into drug repurposing. Epidemiological data can offer enticing leads. Yet, clinical trials for these drugs are costly, but the benefits can be huge. The Drugs for Neglected Diseases Initiative, a Swiss non-profit research group, supported research into fexinidazole, which was abandoned by a pharma at an early stage. The drug showed to have antiparasitic qualities. However, after years of work in January 2020, it was approved for sleeping sickness in the Democratic Republic of Congo. It is the first oral medicine for the disease, and works for all stages of it.

Up till now, when it comes to cancer the most promising generic pills are known. Cancer Research, a UK based charity is testing aspirin to see if can stop cancer from recurring; metformin in a large prostate-cancer trial; and an anti-fungal medication to treat bowel cancer. At the same time, the Anticancer Fund in Brussels hopes that propranolol in treating cancers of the inner lining of blood vessels and pancreatic cancer. Propranolol is a generic 1960s beta-blocker used for a wide range of ailments such as hypertension, anxiety and migraine. If approved for cancer, its cost would be negligible in comparison the tens of thousands of dollars a month usually charged for cancer medicines.

Money seems the crucial constraint with these drugs, in addition to the clinical trials needed to have these drugs updated and relabeled. Only the makers or original developers of a drug are permitted to adjust its label. Sanofi, based in Paris, was the firm that requested regulatory review of fexinidazole for sleeping sickness, while the research was a charitable effort. But drug firms are not forced to support non-commercial efforts to repurpose drugs. And outside the industry it is tough to find the legal expertise to be able to do the  necessary paperwork.

As non-profits make progress in repurposing, corporate interest may be rising. In terms of achieving new treatment options, this is good news. But it will not bring cheaper medicines in areas traditionally neglected by the drug industry. Firms will focus on finding ways to patent the new uses and charge high prices for the finished product.

If governments need cheaper drugs, non-profits will need financial incentives and a cooperative regulatory framework. They include making regulators give free advice and waive approval fees, and a public fund to support repurposing. Yet, when drugs are approved, investors are paid back by the public health service, which makes savings by using the newly approved generic drugs.




Other related articles published in this Online Scientific Open Access Journal include:


The Castleman Disease Research Network publishes Phase 1 Results of Drug Repurposing Database for COVID-19

Reporter: Stephen J. Williams, PhD


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Real Time Coverage @BIOConvention #BIO2019: Chat with @FDA Commissioner, & Challenges in Biotech & Gene Therapy June 4 Philadelphia

Reporter: Stephen J. Williams, PhD @StephenJWillia2


  • taking patient concerns and voices from anecdotal to data driven system
  • talked about patient accrual hearing patient voice not only in ease of access but reporting toxicities
  • at FDA he wants to remove barriers to trial access and accrual; also talk earlier to co’s on how they should conduct a trial

Digital tech

  • software as medical device
  • regulatory path is mixed like next gen sequencing
  • wearables are concern for FDA (they need to recruit scientists who know this tech


  • must address the crisis but in a way that does not harm cancer pain patients
  • smaller pain packs “blister packs” would be good idea

Clinical trial modernization

  • for Alzheimers disease problem is science
  • for diabetes problem is regulatory
  • different diseases calls for different trial design
  • have regulatory problems with rare diseases as can’t form control or placebo group, inhumane. for example ras tumors trials for MEK inhibitors were narrowly focused on certain ras mutants
Realizing the Promise of Gene Therapies for Patients Around the World

103ABC, Level 100

Lots of promise, timeline is progressing faster but we need more education on use of the gene therapy
Regulatory issues: Cell and directly delivered gene based therapies have been now approved. Some challenges will be the ultrarare disease trials and how we address manufacturing issues.  Manufacturing is a big issue at CBER and scalability.  If we want to have global impact of these products we need to address the manufacturing issues
 of scalability.
Pfizer – clinical grade and scale is important.
Aventis – he knew manufacturing of biologics however gene therapy manufacturing has its separate issues and is more complicated especially for regulatory purposes for clinical grade as well as scalability.  Strategic decision: focusing on the QC on manufacturing was so important.  Had a major issue in manufacturing had to shut down and redesign the system.
Albert:  Manufacturing is the most important topic even to the investors.  Investors were really conservative especially seeing early problems but when academic centers figured out good efficacy then they investors felt better and market has exploded.  Now you can see investment into preclinical and startups but still want mature companies to focus on manufacturing.  About $10 billion investment in last 4 years.

How Early is Too Early? Valuing and De-Risking Preclinical Opportunities

109AB, Level 100

Valuing early-stage opportunities is challenging. Modeling will often provide a false sense of accuracy but relying on comparable transactions is more art than science. With a long lead time to launch, even the most robust estimates can ultimately prove inaccurate. This interactive panel will feature venture capital investors and senior pharma and biotech executives who lead early-stage transactions as they discuss their approaches to valuing opportunities, and offer key learnings from both successful and not-so-successful experiences.
Dr. Schoenbeck, Pfizer:
  • global network of liaisons who are a dedicated team to research potential global startup partners or investments.  Pfizer has a separate team to evaluate academic laboratories.  In Most cases Pfizer does not initiate contact.  It is important to initiate the first discussion with them in order to get noticed.  Could be just a short chat or discussion on what their needs are for their portfolio.

Question: How early is too early?

Luc Marengere, TVM:  His company has early stage focus, on 1st in class molecules.  The sweet spot for their investment is a candidate selected compound, which should be 12-18 months from IND.  They will want to bring to phase II in less than 4 years for $15-17 million.  Their development model is bad for academic labs.  During this process free to talk to other partners.

Dr. Chaudhary, Biogen:  Never too early to initiate a conversation and sometimes that conversation has lasted 3+ years before a decision.  They like build to buy models, will do convertible note deals, candidate compound selection should be entering in GLP/Tox phase (sweet spot)

Merck: have MRL Venture Fund for pre series A funding.  Also reiterated it is never too early to have that initial discussion.  It will not put you in a throw away bin.  They will have suggestions and never like to throw out good ideas.

Michael Hostetler: Set expectations carefully ; data should be validated by a CRO.  If have a platform, they will look at the team first to see if strong then will look at the platform to see how robust it is.

All noted that you should be completely honest at this phase.  Do not overstate your results or data or overhype your compound(s).  Show them everything and don’t have a bias toward compounds you think are the best in your portfolio.  Sometimes the least developed are the ones they are interested in.  Also one firm may reject you however you may fit in others portfolios better so have a broad range of conversations with multiple players.



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FDA Guidelines For Developmental and Reproductive Toxicology (DART) Studies for Small Molecules. Author-Writer: Stephen J. Williams, Ph.D.

This posting is a follow-up on the Report on the Fall Mid-Atlantic Society of Toxicology Meeting “Reproductive Toxicology of Biologics: Challenges and Considerations post and gives a brief synopsis of the current state of FDA regulatory guidelines with respect to DART studies on small molecule (non-biological based) therapeutics.    The following is adapted from the book Principles and Methods of Toxicology by Dr. A Wallace Hayes (1) and is an excellent reference on reproductive toxicology and testing methods.

Chemical insult occurs to the human reproductive system at a multitude of stages in development and the life cycle, leading to the extensive testing which must be performed to diligently the reproductive and development toxicity of a chemical/drug.  Abnormalities and toxic manifestations in the offspring may result from insult to the adult reproductive (either female or male) and neuroendocrine systems, as well as damage to the embryo resulting in embryolethality, fetus at any period during organogenesis, juvenile development or, in the case of certain antibody therapies, immune system development.  The latter, toxic insult to the developing immune system could possibly be manifested as either an immune defect in the newborn or, later in life, as tolerance to said therapy.  It is estimated that exposure to the pregnant woman, of either environmental contaminants or drug, is significant.  It is estimated that a mother may be taking an average of 8-9 different drug preparations, mostly over the counter preparations such as antacids, vitamin preparations, cathartics etc. with the maximal drug intake occurring between 24 and 36 weeks of gestation.

Toxic insult to the developing embryo is dependent on

  • Fetal development stage during drug/chemical exposure
  • Maternal/placental xenobiotic metabolism
  • Pharmacokinetic parameters affecting bioavailability and fetal/maternal drug binding

The following table shows the dependency of developmental stage to teratogenicity: adapted from J. Manson, H. Zenick, and R.D. Costlow from Principles and Methods of Toxicology.

Developmental Stage Major Susceptibility
Preimplantation Embryolethality
Organogenesis Births defects; embryolethality
Fetal Growth retardation, fetal death, functional deficits
Neonatal Growth retardation, nervous system alterations, immune and endocrine systems

It is not generally accepted that there is a dose dependency of teratogenesis however most teratogens have specific mechanisms of action and teratogenic effects occur at much lower doses than result in maternal toxicity.   However, the developmental toxicity may be manifested later in life, including as reproductive toxicity affecting adult fertility and familial generations.

FDA Guidelines for DART Studies on Non-Biologics (Small Molecule Therapeutics)

The basic design for DART studies incorporate the aforementioned principles of tetralogy:

  • developmental stage of fetal exposure
  • parental effects on reproduction and development
  • toxicity may be manifested over multiple generations including fertility rates

Therefore two designs are generally used for DART studies

  1. exposure across several generations
  2. exposure during one generation

FDA requires one control group and two treatment groups, and evaluation of at least two species.  However, most studies will use two rodent and one nonrodent species.

Multigenerational Design

Multigenerational DART studies are conducted for compounds likely to concentrate in the body following long-term exposure.  Examples of types of compounds include pesticides and food additives.

Figure 1.  General Design of a Multigenerational DART study.  Weanlings (30-30 days of age) from the parental generation are treated for a period up to 60 days. At 100-120 days of parental generation, animals are mated.  Fx = filialx .

Three Segment, Single Generation Tests

The single generation design is more suitable for DART studies on drugs, as most therapeutic would be taken over short periods (during pregnancy) and have relatively short half-lives in the body.  FDA guidelines separate these studies in three phases:

I.            Phase I: evaluation of fertility and general reproductive performance

II.            Phase II: assessment of teratogenicity and embryotoxicity

III.            Phase III: peri- and postnatal evaluations.

All figures are adapted from Principles and Methods of Toxicology.(1)

FDA guidelines Guidance for Industry Reproductive and Developmental Toxicities —Integrating Study Results to Assess Concerns can be found at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079240.pdf

FDA Guideline for reproductive toxicity testing for small molecule therapeutics can be found at:


1.            Hayes, A. W. (1986) Principles and Methods of Toxicology, Raven Press, New York

Other research papers on Pharmaceutical Intelligence and Reproductive Biology, Bio Insrumentation, Endocrinology Genetics were published on this Scientific Web site as follows

Non-small Cell Lung Cancer drugs – where does the Future lie?

Reboot evidence-based medicine and reconsider the randomized, placebo-controlled clinical trial

Every sperm is sacred: Sequencing DNA from individual cells vs “humans as a whole.”

Leptin and Puberty

Gene Trap Mutagenesis in Reproductive Research

Genes involved in Male Fertility and Sperm-egg Binding

Hope for Male Contraception: A small molecule that inhibits a protein important for chromatin organization can cause reversible sterility in male mice

Pregnancy with a Leptin-Receptor Mutation

The contribution of comparative genomic hybridization in reproductive medicine

Sperm collide and crawl the walls in chaotic journey to the ovum

Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations

Biosimilars: CMC Issues and Regulatory Requirements

Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

Assisted Reproductive Technology Cycles and Cumulative Birth Rates

Innovations in Bio instrumentation in Reproductive Clinical and Male Fertility Labs in the US

Increased risks of obesity and cancer, Decreased risk of type 2 diabetes: The role of Tumor-suppressor phosphatase and tensin homologue (PTEN)

Guidelines for the welfare and use of animals in cancer research

Every sperm is sacred: Sequencing DNA from individual cells vs “humans as a whole.”

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Report on the Fall Mid-Atlantic Society of Toxicology Meeting “Reproductive Toxicology of Biologics: Challenges and Considerations.  Author, Reporter: Stephen J. Williams, Ph.D.

The fall 2012 Meeting of the Mid-Atlantic Society of Toxicology (MASOT) focused on the challenges and solutions in developing proper Development and Reproductive Toxicology (DART) studies with regards to the newer classes of bio-therapeutics such as vaccines, antibody-based therapies, and viral-based therapies.  The full meeting and MASOT links can be found at http://www.masot.org.   The overall synopsis of the meeting talks agreed, that although the general aim and design of DART studies for biological are very similar to DART studies for small molecule therapeutics, it is more necessary to take into consideration the pharmacodynamics, pharmacokinetic differences between biologics and small molecules.   In addition it is imperative to use pharmacologically-relevant species, such as non-rodent (guinea pig and non-human primate). The meeting was highlighted by the keynote speaker, Dr. A. Wallace Hayes, renowned board-certified toxicologist, committee and expert panel member for National Academy of Sciences, NIEHS, EPA and Department of Defense, and editor of well-known textbooks including Principles and Methods of Toxicology.  Dr. Hayes discussed a timeline of milestones in the field of toxicology.

The following are the meeting talk abstracts as well as notes for each presenter.

What’s So Different About DART Assessment of Biologics? Christopher Bowman Ph.D., DABT (Pfizer, Inc.)

Abstract:  The aim of developmental and reproductive toxicity (DART) safety assessment of a biologic is no different from that of a small molecule. Both cases consist of evaluating the potential for maternal toxicity, pre- and postnatal development toxicity (including juvenile toxicity) and effects of fertility (reproduction).  The differences lie in the in the product attributes of a specific biologic, the pharmacological response, the potential for undesirable toxicities and how these product attributes influence and are influenced by the biology.  Thus the primary challenge for developing a DART strategy for a biologic are derived from the complexities of these biomolecules and how that dictates a case-by-case strategy for appropriately evaluating the potential for developmental and reproductive toxicity. Most protein biologics have very limited potential for off-target toxicities, but this is not necessarily the case for other modalities such as anti-sense oligonucleotides and antibody-drug-conjugates.  In these cases, off-target toxicities can be a major feature of the DART safety assessment.  The most noticeable difference in DART assessment of biologics is the need to conduct these studies in pharmacologically relevant species and how that can influence the overall nonclinical strategy (including DART).  This has led to increased use of non-human primates as a model system and led to optimizations of this model for this purpose and revisions to international guidelines.

Notes:   Dr. Bowman emphasized the need to understand the type of biological you are testing and to both devise DART studies based on this information, additional endpoint you may want, as well as carefully choosing the correct species most relevant to the biologic.  He highlighted general differences between small molecules versus a biologic with respect to their pharmacology.  These differences are summarized in the Table below:

  Small Molecule Biologic-based therapy
Species specificity Low High
Route of administration Usually oral Parental
ADME (PK, bio-distribution etc.) Wide distribution Low distribution

He noted that clinical trials for biologics rarely include reproductive toxicity so the preclinical DART study is of utmost importance.  He also emphasized that currently, the FDA requires two species for DART testing of small molecule therapies (usually one rodent and one non-rodent).  However this is not possible with many biologics as species is to be taken in consideration when designing a meaningful DART study.  Study designs can be like most DART studies but want to have a steady exposure during fetal organogenesis, use high doses (10 times the clinical dose) to achieve maximal pharmacology, confirm exposure to fetus and to F1 generation, and determine embryolethality.  Some biologics like interferon and insulin-growth factor receptor (IGFR) antagonists are fetal abortifactants. In fact Lucentis (Ranibizumab) and Macugen (Pegaptanib) were approved with no or little DART studies, however these drugs showed reproductive toxicity, resulting in warning concerning pregnancy on the label. Also important is the effect on the immune system and reproductive system of offspring, as well as the pharmacodynamics profile in the offspring.

Species Selection for Reproductive and Developmental Toxicity Testing of Biologics; Elise M. Lewis, Ph.D. (Charles River Preclinical Services)

Abstract:  Regulatory guidelines for developmental and reproductive toxicology studies require selection of “relevant” animal models as determined by kinetic, pharmacological, and preceding toxicological data.  Rats, mice, and rabbits are the preferred animal models for these studies based on historical experience and well-established procedures and study protocols.  However, due to species specificity and immunogenicity issues, developmental and reproductive toxicology testing for biologics is limited to a pharmacologically relevant animal model as described in the ICH s6 guideline.

Notes:  Dr. Lewis notes that DART studies in guinea pigs and hamsters represent a cost effective alternative to large animal models as well as the benefit of shorter duration and ability to assess mating behavior.  She also notes that reproductive toxicology of vaccines should be done in an animal model that can elicit an immune-response to the vaccine, especially to determine any maternal-fetal interaction.  For example, a vaccine may be directed to a maternal protein which when suppressed, may negatively impact the developing fetus.  However it is important to remember that guinea pigs can spontaneously abort so it is good to have proper control arms of a substantial size in order to statistically determine the impact of those spontaneous abortions.



Placental Transfer of an Adnectin Protein During Organogenesis in Guinea Pigs Using a Radiolabeled Methodology; Lakshmi Sivaraman, Ph.D. (Bristol-Myers Squibb)

Abstract:  Knowledge regarding the placental transfer of large molecular weight therapeutics is important to support the enrollment of women of childbearing potential in clinical trials.  There is limited information in the scientific literature that reports the extent to which the conceptus is exposed to these large molecules during organogenesis.  Placental transfer of large therapeutics has been difficult to quantify, due to limited blood volumes that can be obtained from the embryo, as well as insufficient assay sensitivity.  Thus, it is possible that embryos are exposed to pharmacologically active concentrations after maternal drug exposure. We have adopted a radiolabeled approach to quantitate embryo-fetal exposure of a novel protein therapeutic platform (adnectins). Adnectins are fibronectin-based proteins containing domains engineered to bind to targets of therapeutic interests.

Notes: Adnectins molecular weight is typically less than monoclonal antibodies and while IgG is not transferred in great quantity past the placental barrier there have been studies in human indicating maternal-fetal transfer of monoclonal antibodies.  This is particularly important for two reasons:  the monoclonal interacts with a target important in development, or the fetal immune system could be augmented.  Their work will be published in Drug Metabolism and Disposition.  In general Dr. Siveraman engineered a radiolabel on adnectin and used different detection methods to quantify the fetal exposure to a single maternal dose.  Dr. Siverman was able to detect radiolabel in the fetus however it is not clear whether this is a significant amount.

Reproductive Toxicity Testing for Biological Products in Nonhuman Primates: Evolution and Current Perspectives: Gary J. Chellman, Ph.D., DABT (Charles River Preclinical Services)

Notes:  Dr. Chellman gave a review of the current trends being driven by regulatory agencies with regard to nonhuman primate DART studies of biopharmaceuticals.  He noted that an advantage using nonhuman primates were the close physiologic resemblance to humans and because a large animal could monitor pregnancy over time using ultrasound technology.  In general, Dr. Chellman spoke about new study designs which not only reduce the number of animals required but also significantly reduce costs.  For example, a DART study which cost upward of $750,000 now can be done for as little as $350,000.  Dr. Kary Thompson of Bristol Myers Squibb then gave a talk about use of these new enhanced designs to determine reproductive toxicity issues with ipilimumab (Yervoy).

Other research papers on Pharmaceutical Intelligence and Reproductive Biology, Bio Insrumentation, Endocrinology Genetics were published on this Scientific Web site as follows

Non-small Cell Lung Cancer drugs – where does the Future lie?

Reboot evidence-based medicine and reconsider the randomized, placebo-controlled clinical trial

Every sperm is sacred: Sequencing DNA from individual cells vs “humans as a whole.”

Leptin and Puberty

Gene Trap Mutagenesis in Reproductive Research

Genes involved in Male Fertility and Sperm-egg Binding

Hope for Male Contraception: A small molecule that inhibits a protein important for chromatin organization can cause reversible sterility in male mice

Pregnancy with a Leptin-Receptor Mutation

The contribution of comparative genomic hybridization in reproductive medicine

Sperm collide and crawl the walls in chaotic journey to the ovum

Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations

Biosimilars: CMC Issues and Regulatory Requirements

Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

Assisted Reproductive Technology Cycles and Cumulative Birth Rates

Innovations in Bio instrumentation in Reproductive Clinical and Male Fertility Labs in the US

Increased risks of obesity and cancer, Decreased risk of type 2 diabetes: The role of Tumor-suppressor phosphatase and tensin homologue (PTEN)

Guidelines for the welfare and use of animals in cancer research

Every sperm is sacred: Sequencing DNA from individual cells vs “humans as a whole.”



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New England Compounding Center (NECC): Tracking the Sources of Fungal Infections

Reporter: Alan F. Kaul, R.Ph., Pharm.D,, M.S., M.B.A, FCCP

The cause of the outbreak or fungal infections caused by contaminated steroids prepared by NECC has now been confirmed and treatment guidelines for those patients affected are in place.  Unfortunately, the toll in human lives and suffering cannot be rectified.  Clearly, compounding pharmacies are licensed by each state to produce products to meet individual patient needs. They are not legally licensed to manufacture drugs for mass distribution as is a pharmaceutical manufacturer that is licensed and inspected by the FDA.

The question of how to preclude further human disasters such as this is not yet resolved.  Painting all compounding pharmacies as unreliable as some have suggested does an enormous discredit to those pharmacists operating safe and reliable facilities where sterility testing meets or exceeds recommended standards. Political grandstanding also does a disservice towards working towards a viable answer. Should the Pharmacy Compounding Accreditation Board (PCAB), an organization that inspects and certifies that its members meet or exceed USP Chapter 797 standards be given deemed status like The Joint Commission or other similar accrediting organizations to accredit compounding pharmacies? Should state Boards Of Registrations in Pharmacy of Public Health Departments be funded for additional staff to monitor and inspect sterile compounding pharmacies? If so, will the additional expense be paid by the state, the compounding pharmacies, or the patients requiring the specially prepared drugs? Ultimately, the taxpayers will be required to pay for the requisite safeguards.  While the answer is still unresolved, careful though should be given to all possible options including a combination of them in moving forward.  The status quo is not an acceptable solution to meet the needs of providing safe and effective drugs to the public.

Investigations have now confirmed that NECC is the pharmacy linked to the deadly outbreak of fungal infections caused by Exserohilum rostratum, Aspergillus fumigatus, and Cladosporium species. An estimated 14,000 patients in 23 states received steroidal injections between May 21 to September 26, 2012 from lots of drugs prepared by NECC on May 21, June 29, and August 10, 2012. These three suspected lots of drugs prepared from steroids contained 17,676 doses were shipped to 75 locations. Three hundred forty-four infections including meningitis and those of the joints and 25 deaths have been attributed to the contaminated drugs.  As of October 22, 2012, there were 54 patients with CDC confirmed fungal meningitis. Of those, 52 were due to Exserohilum rostratum and one each due to Aspergillus fumigatus, and Cladosporium species.

Several hospitals including Saint Joseph Mercy Ann Arbor Hospital (Ypsilanti, MI), a Baltimore-area emergency room, Saint Thomas Hospital (Nashville, TN) independently noted patients presenting with symptoms including headaches, sensation to light, and neck stiffness, vertigo, double-vision, and loss of muscle co-ordination. In some patients, spinal taps were suggestive of meningitis and treatment was begun. However, infectious disease specialists were unable to identify the pathogen causing the infections. In late summer, across the United States, the same pattern appeared; patients with life-threating infections and an unknown cause. In North Carolina, a 77 year-old generally healthy female patient received the third of thee epidural injections for back pain. In September, she began experiencing terrible headaches. After multiple trips for medical care and being misdiagnosed with migraines and undergoing a brain scan, a family member insisted that she be hospitalized until they could diagnose her illness. A spinal tap was performed and spinal fluid was cultured. Meningitis of an unknown cause was diagnosed.

In Tennessee a man in his 50’s who initially responded to treatment for meningitis and went home returned to Vanderbilt University Medical when his infection reappeared. The patient presented visibly ill and had unintelligible speech. Dr. April Petit an infectious disease specialist ordered the laboratory to test for unusual microbes and also fungi.  The later generally is found in immunocompromised patients. The laboratory reported that the cerebrospinal fluid culture grew Aspergillus.  After again reviewing the patient’s medical history, Dr. Petit noted that the patient had received an epidural steroid injection at the Saint Thomas Outpatient Neurosurgery Center several weeks prior to the onset of his symptoms.  She contacted the Tennessee Department of Health on September 18.

The TN Department of Health contacted Saint Thomas infection prevention staff and learned that another patient who had received an epidural steroid injection at the same facility followed a similar clinical path. Saint Thomas closed its Outpatient Neurosurgery Department on September 20 and TN notified the CDC.  State health officials in TN conducted an inspection of the Saint Thomas Outpatient neurosurgery Department to try to determine the etiology of the infection. Some considerations included improper infection control procedures, contaminated equipment, and contaminated drug.

Within a few days, several more cases of rare fungal meningitis was identified that developed between July 30 and September 18 and the TN Department of Health notified the MA Department of Public Health. The patients shared four commonalties, one being that they ad received an injection of methylprednisolone acetate manufactured by NECC.  On September 25, MA state regulators requested NECC provide a list of all medical centers that had received shipments of the suspect steroid.  They learned that the three suspect lots of drugs totaling 17,676 doses had been shipped to 75 centers.

As the CDC conducted its investigation of sites that had received the drug, they learned that other cases outside of TN had occurred including North Carolina and Michigan.  The CDC issued a health advisory.  Because of the rarity of fungal meningitis, few researchers and clinicians were accustomed to dealing with it. CDC convened an expert advisory panel to develop recommended treatment guidelines.  In addition to the initial discovery of Aspergillus fumigatus, thesubsequent cases were discovered to be caused principally by the black mold, Exserohilum rostratum.  Experts concurred that while cases caused by the former fungus were rare, cases caused by the later were even rarer and treatment options were not well identified. Many effected patients were elderly and had other co-morbidities further complicating distinguishing symptoms and making the choice of pharmacotherapy with drugs often associated with serious side effects even more difficult.

Multidisciplinary teams quickly developed expertise at Saint Joseph Mercy Ann Arbor where 66 patients were being treated.  The team included the Chief Medical Officer, pharmacists, emergency room physicians, infectious disease specialists convened for daily discussions and updates.  Drug regimens for each patient were finely tuned and a special clinic was opened to assist patients in managing their disease.

As the saga continued, more patients in multiple states were identified and treated. Unfortunately, the epidemic had already taken its grim toll.



The United States Food and Drug Administration (FDA) continues to reiterate that there should be follow-up with patients who meet the following three conditions:

  1. The medication used was an injectable product purchased from or produced by NECC, including an ophthalmic drug that is an injectable used in conjunction the eye surgery, or a cardioplegic solution,
  2. The medication was shipped by NECC on or after May 21, 2012, and
  3. The medication was administered on or after May 21, 2012.

On October 22, 2012, the FDA made available a list of customers (no product information available) of NECC from May 21, 2012 sorted by state which can be found at:


On October 23, 2012, the Centers for Disease Control and Prevention (CDC) issued a an Official Health Advisory Issuance of Guidance on Management of Asymptomatic Patients Who Received Epidural or Paraspinal Injections with Contaminated Steroid Products. CDC continues to recommend against treating using antifungal prophylaxis for treating exposed asymptomatic patients without a diagnostic testing indication meningitis. They indicate that the greatest risk of developing an infection is within the first six weeks 942 days) after injection. As an increased benefit from prophylaxis has not been demonstrated from currently available data, additional monitoring of these patients should be considered.



Outbreak baffled doctors until they saw common cause

By  Carolyn Y. Johnson   |   G L O B E S T AF F        O C T O B E R  2 8 ,  2 0 1 2


Rhonda Hall, who had a steroid injection, talked with Anurag Malani, infectious disease specialist at a

Michigan hospital.

It was Labor Day weekend when the first patients began to trickle into an Ypsilanti, Mich., hospital complaining of headaches, sensitivity to light, and neck stiffness. Laboratory tests of the patients’ spinal fluid strongly suggested meningitis and physicians started treatment.

But in a cluster of offices on the third floor, four of Saint Joseph Mercy Ann Arbor Hospital’s infectious disease specialists wrestled with a puzzle: Why couldn’t the laboratory identify the microbe causing the infection?

 Later that week and some 500 miles away, a 51­ year­ old woman developed a powerful headache radiating into her face and headed to a Baltimore ­area emergency room. She was discharged after a normal brain scan, but returned the next day with distressing symptoms: double vision, nausea, vertigo, and a loss of muscle coordination. As her condition worsened, a spinal tap provided no clues to the underlying cause.

And then in mid­ September, Dr. Robert Latham at Saint Thomas Hospital in Nashville, Tenn., found himself perplexed by the case of a woman who returned to the hospital after a treatment for meningitis stopped working. Lab tests showed signs of a raging infection, but similarly, he could not identify the culprit.

At hospitals scattered across the country, it was the horror story of the waning days of summer. Teams of physicians faced the same medical mystery — patients with life­ threatening infections with an unknown cause. There were subtle hints that they were dealing with a highly unusual illness, and astute clinicians and state and federal health officials worked to connect the dots. Ultimately, they would discover that these seemingly isolated cases were the leading edge of an outbreak of a fungal meningitis so rare that many doctors will never see a case in their lifetimes.

 The cases would quickly be linked to three batches of an injected steroid produced by a Framingham compounding pharmacy, but by that time 14,000 people in 23 states had received the injections for back and joint pain. More than 300 have fallen ill, and 25 have died.

Still immersed in treating the illness, most doctors have not had time to reflect on it. But Latham compared the initial confusion, frustration, and growing alarm to the early 1980s, before HIV had been identified as the cause of AIDS. The impact of a tainted drug could never be compared to that global epidemic, but at Saint Thomas, where 38 patients have now been treated, the medical team had the same feeling of being overwhelmed by an unknown that was bigger than anyone imagined.

 “When the HIV patients first started presenting, we were all scratching our heads, saying, ‘What in the devil is this?’ ” Latham said. “Those of us here at Saint Thomas are having an experience similar to San Francisco General in the early 1980s, when young men were walking in” with pneumonia and cancer.

This time, the patients walking in were mostly middle­age and elderly, with signs of meningitis.

The struggle for answers

Elwina Shaw of Denton, N.C., received the third of a set of epidural injections for back pain at the end of August. A vibrant 77­year­old, Shaw was generally healthy, said her daughter, Dawn Frank, aside from a little bit of knee pain and the back trouble. She wanted back surgery, but she had been steered instead toward the shots to see whether they would help.

Shaw was working in her garden one day in September when she got a terrible headache, Frank recalled. Shaw went to the doctor, and at first was told she was having migraines. But they didn’t go away. She went to the hospital for a brain scan, but it still wasn’t clear what was wrong. She was sent home, Frank said, and was told it might be a virus.

Finally, on September 25, Frank brought her mother back to the hospital, determined that doctors would not send her away until they could figure out what was wrong. Near midnight, she remembers, they did a lumbar puncture, drawing out a sample of spinal fluid.

Frank prayed it would not be bad. Shaw’s 80 ­year ­old husband, Rex, needed her. A talented seamstress, eloquent writer, and a woman of great faith, she filled their home and lives with grace and love. She never drew attention to herself, and had always embraced being a homemaker and mother.

 The test results were clear: meningitis of unknown cause. Unbeknownst to her physicians and her family, Elwina Shaw had joined the constellation of cases that were challenging doctors and wrenching families in other states.

In Michigan, patients who responded initially to treatment for meningitis returned to the hospital, worse. In Maryland, the 51­year­old woman’s spinal fluid was tested for bacterial infection and viruses ranging from West Nile to herpes as medical teams tried to treat her, according to a report published in the  Annals of Internal Medicine . Within a week and a half of being admitted to the hospital, she was brain dead. In Tennessee, doctors were struggling to figure out how to help the woman who had seemed to recover, then relapsed.

Dr. Varsha Moudgal, an infectious disease specialist at Saint Joseph Mercy Ann Arbor in Michigan, said physicians there had been mulling over several unusual aspects of their handful of cases. Some patients seemed almost too well, Moudgal said, explaining that meningitis patients with the kind of sky­high counts of immune cells and extremely low glucose levels doctors measured would typically have more symptoms, such as altered mental abilities.

“They came in and didn’t appear to be as ill as their cerebrospinal fluid picture suggested,” Moudgal said. “They were talking to us. They were sitting up.”

Others had severe symptoms but their lab tests suggested their infections were not that bad.

The doctors turned to specialists in microbiology and pathology, asking them to rack their brains for better diagnostic methods. Physicians scoured the medical literature to see whether past cases could teach them how to treat their growing cluster of patients. Dr. Anurag Malani said he heard rumbles of a case at another hospital that echoed theirs.

“We knew something was wrong, but it was hard to put a finger on it,” Malani said. “In hindsight, I think a lot of other places were feeling the same frustration.”

Meanwhile, in Tennessee, Dr. April Pettit, an infectious disease specialist at Vanderbilt University Medical Center, had been struggling with the same disturbing pattern: A man in his 50s with what appeared to be meningitis. He initially responded to treatment, went home, and then returned, the infection careening out of control.

 When he came back, she reported in the  New England Journal of Medicine this month, he was visibly ill and his speech unintelligible. Searching for answers, she told the laboratory to test for unusual microbes, such as fungi, even though such infections are quite rare, usually occurring in people with suppressed immune systems.

“On morning rounds, Dr. Pettit gets a call from the microbiology laboratory,” said Dr. William Schaffner, an infectious disease specialist at Vanderbilt who is familiar with the case. “She steps out to get the call, and she receives the information the cerebrospinal fluid has grown a fungus: aspergillus. She is dumbfounded.”

A common denominator

Pettit reviewed her patient’s history, to see whether there was anything unusual, anything that could explain why an otherwise healthy, middle­aged man with no immune system problems could have gotten such a rare type of meningitis. Several weeks earlier, she learned, he had received an epidural steroid injection at Saint Thomas Outpatient Neurosurgery Center. It was the only thing that stood out. She contacted the Tennessee Department of Health.

Dr. Marion Kainer of the health department immediately got in touch with the infection prevention staff at Saint Thomas. She told them of the man in his 50s, whose disease had followed much the same trajectory as their patient — and who had also received an injection. Latham knew his patient had also gotten an epidural injection at the hospital’s neurosurgery clinic, but previously he had no reason to connect it to her symptoms.

“The fact we had two people with strange presentations, related to the epidural injection, I hope would have been a bellwether for us,” Latham said. But that day, they got an even clearer message that something larger was going on: Another person had been admitted with similar symptoms. That person had also had an injection at the same place.

Saint Thomas closed its Outpatient Neurosurgery Center on Thursday, Sept. 20, and Tennessee notified the Centers for Disease Control and Prevention in Atlanta. Latham accompanied state health officials on an inspection of the facility to see whether there were any clues as to where the infection had come from: Did the clinic have the proper infection ­control policies and procedures? Was there a chance equipment had been contaminated? Could it have been a contaminated drug?

 By that Sunday, other probable cases had been identified in Tennessee, and the next day the Tennessee Department of Health contacted their counterparts in Massachusetts. Late in the evening, the Tennessee officials told the Bay State regulators of six rare fungal meningitis cases that had developed between July 30 and Sept. 18 in their state. The patients had at least four things in common: one being that they had received an injection of methylprednisolone acetate made by New England Compounding Center.

A day later, state regulators asked the owners of the Framingham compounding pharmacy to compile a list of all the medical centers that had been shipped medication from three batches of the steroid that federal officials had flagged as suspicious. The lots, prepared on May 21, June 29, and Aug. 10, the officials learned, had been shipped to 75 locations — and they contained 17,676 doses.

The next day, Sept. 26, the company voluntarily recalled the products, but there was still no firm connection between the drugs and the outbreak.

Then, physicians at the High Point Regional Health System in North Carolina, where Elwina Shaw was being treated, received a call from the CDC. The High Point Surgery Center was among the places that received doses of the drug. The agency official asked whether there were any patients with symptoms similar to the Tennessee cases, according to hospital spokeswoman Tracie Blackmon. High Point did have such a patient, the hospital confirmed.

The CDC later said in a health advisory that it was that first case outside of Tennessee that was “possibly indicating contamination of a widely distributed medication.” Frank said her family was told her mother’s case helped point the finger at the contaminated drug. “The steroid was the common denominator,” Frank said.

The doctors in Michigan began to hear news reports of what was going on in Tennessee. They began to realize the common thread was the epidural injections their patients had received at a nearby clinic.

Treating an outbreak

Pinpointing the source of the infection was only the first step. Public health officials now realized that many more people were likely to be hospitalized in the coming weeks, but they had little idea how to treat them. Fungal meningitis occurs infrequently, and the circle of researchers who study such infections is small.

 The CDC convened a panel of experts to develop advice for physicians on what symptoms to watch for, how to best treat it, and when to start antifungal medications. Complicating matters was the fact that while the initial case in Tennessee involved a fungus called Aspergillus fumigatus, the subsequent cases were mainly caused by a black mold called Exserohilum rostratum.

Cases of meningitis caused by aspergillus were rare, say specialists in fungal diseases, but cases caused by black mold were even more so, making the outbreak almost entirely untrodden medical ground. The large number of elderly victims was another challenge, because many had chronic conditions that could make it difficult to distinguish symptoms or that make them unable to tolerate the harsh drugs.

Expertise rapidly developed at the centers that were hardest hit. At Saint Joseph Mercy Ann Arbor, where 66 patients had been treated as of Friday, there was a daily 9 a.m. “huddle” of health care providers, followed by a call that drew together people from across the hospital, from the chief medical officer to pharmacists to emergency room doctors to the infectious disease specialists.

Drug regimens were fine­tuned to diminish side effects, and a special clinic was set up to help patients manage the disease.

Patients will have to take the antifungal drugs for a minimum of three months — and possibly as long as a year.

More staff were brought in to help manage the flood of people who came to be tested for meningitis. On their busiest day, 66 spinal taps were drawn; during the last month, a couple hundred have been performed, Malani said.

Three patients have died, but two fell ill before the meningitis cases were connected to a fungus.

By the time Rhonda Hall showed up at the hospital a week and a half ago, systems and procedures were in place and the pace had slowed. The 49­year­old bus driver from Brighton, Mich., was in an accident a year ago that still causes her pain. She had recently had surgery on her left ankle and got a steroid injection in her hip.

Soon after, Hall found herself clutching the side of her mattress just to get out of bed, and she realized that it wasn’t just an after­effect of the surgery. Something was wrong with her hip.

After hearing about the contaminated injections on the news, she called and learned she had gotten one of the bad shots. She was diagnosed with a bone infection.

“I was very scared in the beginning,” Hall said last week, just before going into surgery to flush out the infected joint. “Now it’s to the point . . . I want it over with so I can start healing and feeling better.”

The lessons learned by physicians came too late for Elwina Shaw. During her time in the North Carolina hospital, Shaw had two strokes, her daughter said, but she was able to write her name in cursive and walk afterward. Her family was hopeful.

But her condition worsened, and she died Friday, Oct. 19. On that day, the CDC reported that 271 people were infected, 21 deceased.

Carolyn Y. Johnson can be reached at  cjohnson@globe.com. Follow her on Twitter



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Reporter: Aviva Lev-Ari, PhD, RN


CEI Headquarters in North Carolina

We are a boutique consulting firm with offices in Research Triangle Park, North Carolina and Boston, Massachusetts, providing primary and secondary research to Life Science organizations. Cutting Edge Information was founded in 2002 by consultants with extensive experience conducting research studies for high-level clients. We put this experience to work to eliminate traditional consulting’s hurdles and focus on producing high-quality information – drawn from top executives at real-world companies – for you and your organization.




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