Thursday, March 3, 2016

Zika Epidemic: Separating Hype from Fact

What is Zika?

It is a virus spread by Aedes mosquitoes - these are the ones that are active during the day. It usually causes no symptoms. In some cases, mild flu symptoms may be produced. But this is often cured with rest. All these are obviously no cause for concern. The reason why the world has taken note is because pregnant women affected by the Zika virus gave birth to babies with small heads. The WHO (World Health Organization) has declared it to be an international public health emergency. After it affected a million people in May 2015, the virus has spread to 24 nations in the Americas and Caribbean, and there is no known vaccine, cure or treatment.
These are the facts surrounding the epidemic.

Does the Zika virus cause microcephaly?

The evidence linking the virus to microcephaly or shrunken heads in newborn babies is at best circumstantial. In Brazil, the transmission of the virus picked up in 2014-15. Up until 2014, the four-year average for microcephaly was 163 cases a year. Brazilian health authorities have now recorded 3,530 cases of microcephaly between October 2015 and January 2016, and this figure includes 46 deaths. But for some reason, most of these have occurred in the northeastern part of the country, leading many to wonder if it is really the Zika virus that is the cause.
The Physicians in the Crop-Sprayed Towns (PCST), a group of doctors, blame it on Pyriproxyfen, a larvicide that was added to Pernambuco’s drinking water supply by the Brazilian Ministry of Health way back in 2014. This was done to check the growth of the Aedes aegypti mosquitoes in the region, after it was determined that these mosquitoes were carriers of the Zika virus. The chemical Pyriproxyfen is known to cause birth defects, and in this immediate instance, a commercial version of it, called SumiLarv, was used. Sumitomo Chemical, believed to be a Japanese subsidiary of Monsanto, produces SumiLarv.
Others are skeptical of this claim. Pyriproxyfen is used in 40 countries worldwide, including developed nations like France, Spain, Denmark and the Netherlands. Recife is the epicenter of the outbreak, but Pyriproxyfen has not been added to the drinking water here. Pyriproxyfen does cause birth anomalies, but because of this, it is added carefully, and only in minutely small quantities, just enough to prevent Aedes aegypti larvae from becoming fully-grown adults. To be at risk from Pyriproxyfen, one would have to drink 1,000 liters of water treated with the chemical. Monsanto also has clarified on its association with Sumitomo – the Japanese company actually supplies it with technology, not the other way around. And this is restricted to herbicides. Monsanto does not own any stake in Sumitomo Chemical. The doctors' group PCST is also an Argentinian organization and not a Brazilian one.

Popular myths surrounding the Zika virus


The most widely circulated of them include how Zika is a killer, like the Ebola virus. The Zika virus is not fatal, and despite over a million being affected, no one has actually died. Those affected need not be hospitalized, and the mild flu-like symptoms pass off in a few days. 

Monday, December 21, 2015

Obituary: Mr. K M Nair

The Chief Controller of RGCB, Mr. K M Nair succumbed to ill-health and passed away on 15th of December, 2015. 

Mr. K M Nair, the former Chief Controller of Rajiv Gandhi Centre for Biotechnology, is no stranger to the executive, legislative or academic fraternity of India. It is very rare for an official to be equally regarded in varied disciplines in a short span of time. Mr. Nair was one of such few widely acclaimed individuals of today. It was, indeed, a great honor for RGCB to have had Mr. Nair as the Chief Controller of the institution.

Mr. Nair had an incredibly prestigious service record spanning over four decades comprising the offices of Assistant Collector of Customs of Trivandrum International Airport, Additional Director General of National Academy of Customs, Excise and Narcotics of Southern Region in Chennai, Additional Director of Enforcement Directorate, Lead trainer for the Ozone Depleting Substances Program of the UNEP and Chief Controller of Vikram Sarabhai Space Centre. He initially joined the Intelligence Bureau in 1974 and was selected to the 1980 batch of India Revenue Service (Customs & Excise). Mr. Nair had an extremely fruitful career, approved by the nation with distinguished accolades at various occasions including President’s Police Medal for Distinguished Service in 1996 and Finance Minister’s Medal for combating tax evasion and smuggling in 1986.

Having attained administrative autonomy under Department of Biotechnology in 2006, the management of RGCB had to undertake cumbersome steps towards wholesome development of the institution. Mr. Nair assigned his office in March 2013. In the short, yet extremely productive two and a half years, he could cast his signature of excellence in all administrative disciplines of the institution. His colleagues remember him as an ever-approachable and sensible person with great words of wisdom. He was always seen taking charge of both administrative and scientific events at RGCB during his tenure. He was known for his humility and principles of righteousness among staff and students alike.

The Director of RGCB, Professor M Radhakrishna Pillai expressed his heartfelt despair to have lost a dear friend and close colleague. With mixed feelings, he shared his joy and pride to have shared official duties with a man of such great esteem and how he had always looked up to Mr. Nair when met with administrative hurdles. RGCB regards this as a moment of incredible loss, yet tries to come to terms with the inevitable changes as wheel of time turns. With immense reverence, the entire RGCB team prays for his soul to rest in peace. 



Government of Kerala offers Guard of Honor to Mr. K M Nair at his funeral on 19th of December, 2015 at Trivandrum.

Tuesday, December 1, 2015

World AIDS Day 2015: A new dawn for HIV treatment

The theme of World AIDS Day 2015 is “Getting to zero; End AIDS by 2030” in unison with the fast track strategies of UNAIDS to end the epidemic of HIV infection by the year 2030. As the federal theme states “The time to act is now” for us.

Devising new health strategies for 2016-2020, World Health Organization (WHO) has recently recommended antiretroviral therapy (ART) right at the time of diagnosis to every single person who gets HIV infection. The current strategy is to treat HIV infected people only when they develop symptoms of AIDS as the infection progresses. WHO also recommends that every individual who is at the risk of exposure to HIV should be given prophylactic antiretroviral therapy. This initiative is a very rigorous step towards proactively containing an infection affecting more than 37 million people worldwide. It is estimated that approximately two million people get newly infected every year. The new strategy brings in an additional 9 million people into antiretroviral eligible category from the existing number of 28 million.

WHO is a co-sponsor of Joint United Nations Programme on AIDS (UNAIDS) which has put forth the recent recommendations hoping to prevent nearly 21 million AIDS related deaths by the year 2030. Current strategies, though meant to address 28 million patients, reach only to 15 million HIV infected people worldwide due to the global challenges in treatment. Not every set of population has accessibility to treatment options. As most of the countries offer antiretroviral therapy free of cost, treating huge numbers of people is a humungous financial burden on governments. Moreover, lack of awareness and social stigma prevent many from seeking help when in need.

UNAIDS has also put forth strict management guidelines to address HIV-TB co-infection as well as to eliminate feto-maternal transmission of HIV. FDA approved treatment modalities available are combination therapies of Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Protease Inhibitors (PIs), Fusion, Entry, Integrase Inhibitors along with Pharmacokinetic Enhancers.

The Union Government of India bears an average cost of Rupees 28,500 to treat one patient with ART. Citing economic constraints, government had strict inclusion criteria for treatable cases. But, after the Supreme Court of India directive to treat every HIV positive patient with complete ART in December 2010, based on “Right to Life” guaranteed by Article 21 of Indian Constitution, it is mandatory for public and private medical sectors of India to offer ART to all patients irrespective of the severity of infection. National AIDS Control Organization (NACO) provides antiretroviral therapy to patients in India through its 91 centers. Though NACO statistics report approximately 2.5 million HIV infected people in India, only 85,000 people receive supervised ART through NACO Centers. This is a major health concern for India.

Health Department of Kerala has set up 36 “Jyothis”- Integrated Counseling and Testing Centers (ICTC) across Kerala to test, counsel and give expert referrals to people free of cost. “Ushus”, supported by NACO, are centers in the Department of Internal medicine at all Medical Colleges of Kerala providing ART free of cost to all HIV positive patients in the state. Kerala is the first state in India to provide free ART to all HIV patients through 42 “Ushus” centers.

Let us all hope the new initiatives by WHO and UNAIDS will help contain this dreadful infection and make human race healthier in near future.

Monday, November 30, 2015

From laboratories to common man: Journey of drug development

As basic scientists in disease biology, we always strive towards an invention or discovery that can make a positive change in existing clinical scenario. We aim to make the life of at least one patient better. From the molecules appearing before us as signals and bands in our basic science experiments to a practical application in clinics is an immensely long journey.

Drug trials are long tedious and meticulous procedures that ensure efficacy and efficiency of drug formulations before they reach market for public use. The odds of a molecule to reach market as a consumable pharmaceutical preparation are approximately calculated to be one in 5000. It takes an estimated average of twelve years for a molecule to travel the long distance between laboratories to market. Here’s a quick peek into the rigorous grilling a molecule undergoes before it “graduates” to be a marketable medication of clinical acceptance.

Preclinical Evaluation: Once a potential therapeutic molecule is identified by in vitro studies in laboratories, it has to undergo preclinical testing in animals to prove its efficacy as well as to document potential side effects. Such a molecule will be considered for further development only if benefits outweigh risks.
Once the preclinical studies are published in effect and not disproved by peers, the patent holders or their collaborating parties can file an Investigation New Drug Application (INDA) to Food and Drug Administration (FDA). Thirty days are given for FDA to consider the implications of developing the molecule concerned to consumable medication. If FDA does not disapprove or reject the application in thirty days, the applicants can proceed with clinical trials of the drug formulation. The application should specify exactly how the formulation will be prepared, number and inclusion/exclusion criteria of study subjects, expected therapeutic and adverse effects and details of the study design and execution.

Phase 0 Study: Before clinical trials begin, a Phase 0 study is carried out to study the pharmacological properties of drug formulation. 10-15 healthy volunteers are given subtherapeutic doses of the formulation to titrate optimum dosage depending on absorption, distribution, metabolism and clearance of the chemical in human body.

Phase I Trials: Once the IND is approved by FDA, applicant parties by themselves or in collaboration with pharmaceutical industry and clinicians can start using the drug formulation on less than eighty healthy volunteers to document in detail potential adverse effects. This is called the Phase I trial, when drug dosage, safe therapeutic window, effective route of administration etc are fine tuned. Moreover, this period is also utilized to study the pharmacokinetics and dynamics including distribution, storage, metabolism, clearance, duration of effect, half life etc. The execution of study and analysis of results may take up to twelve months usually.

Phase II Trials: Once Phase I trials provide favorable results; the formulation can be used in patients with disease for which the drug is intended. This study requires data analytics from about one to three hundred patients. Lasting for about eighteen to twenty four months, these studies look into the dosing of drug formulation in detail. Precise values of minimum and maximum dosages are determined, thus validating a strict therapeutic window of safety. The efficacy of the drug in humans is studied for the first time at this point. An expert team of molecular biologists, biochemists, biostatisticians, pharmacologists and clinicians are directly involved at this stage of the trial. The study is carried out under extremely controlled settings to contain unforeseen adverse effect.

Phase III Trials: Another thirty six to forty eight months are spent to determine therapeutic benefits and potential side effects of the formulation. A randomized controlled study involving multiple hospitals, clinicians, Institutional Ethical Bodies and medical lawyers is carried out to collect data from nearly 3000 patients as test and control subjects to document effects of the drug. Efficiency of the drug formulation to manage targeted pathology is studied at a community level at this point. Equal or perhaps, more attention is given to find out any potential side effects previously undocumented during Phase II trials. The study results should be published in peer-reviewed journals with no conflict of interests of involved parties as well as no dispute from experts in relevant fields. These results also serve as a basis for FDA to analyze risk versus benefits of the drug formulation.
Once Phase III trials show promising results, the involved parties, usually drug manufacturing pharmaceutical giants at this point, file a New Drug Application (NDA) to FDA with data regarding the drug formulation available till date. A typical NDA may easily go from 100,000 to 150,000 pages. Expert committee formed by FDA will then analyze the application unbiased. An estimated time of thirty months is needed for FDA to meticulously analyze all the aspects of the new drug formulation as this goes into market for widespread use across multiple communities once approved at this point.  Unlike clinical trials under controlled settings, the usage of a drug at community level cannot be steered or supervised. Needless to say, extreme caution is therefore taken before formally approving the drug to be produced in large scale for clinical use.

Phase IV Trials; Even after reaching market, a drug is not dispensed completely uncontrolled. Post-marketing Surveillance, also called Phase IV trials are carried out strictly for up to twenty four months and leniently during the entire lifetime of the drug’s medical use to document therapeutic and adverse consequences of the drug formulation at a community level. At this point, the drug is available only as its original formulation, manufactured and marketed only by the party holding patent and FDA approval. One can easily understand why non-generic drugs are expensive as the patent holding drug manufacturer is trying to win back all its expenses of research and development of the formulation as well as the exuberant expenses of conducting multiple phases of drug trials. Drug developers are given patent protection of an original formulation for twenty years in most of the countries. Under special circumstances, a patent term restoration can be given for an additional five years if manufacturers convince FDA for an extended period for clinical data evaluation. This is the period during which manufacturers market the drugs as a brand and earn their invested capital back. This period is also infamously regarded as the period of huge profits for the manufacturer due to their monopoly in markets.

After the patent protected period, other pharmaceutical companies can file an Abbreviated New Drug Application (ANDA) to FDA demonstrating therapeutic equivalence of their formulation to the original brand product. If approved by FDA, the new formulation will be added to Approved Drug Products with Therapeutics Equivalence Evaluations list. This is endearingly called The Orange Book. This is the official approval for the applicant to manufacture and market its formulation as generic drugs. As the capital investment involved in such drug development is much less, generic drugs bring down the price of drugs by about thirty to eighty percent of that of original brand. Moreover, as more manufacturers get bioequivalence approval for their formulation, competition in markets will get stronger, thus forcing companies to slash their prices to sustain demand. This is one noble reason why good quality medications are available even to countries with poor economy without having to sweat much on pharmaceutical research and development.

As we go through the story of a single therapeutic molecule from laboratory to common man, approximately thirty years “smoothly” went past. That’s is one difficult and eventful journey !!!!!