Aiming at increasing notification of all tuberculosis patients and extending patient support services so that eradication of this deadly infectious disease could be achieved by 2025, the central TB division (CTD) of the ministry of health and family welfare has directed state TB officers to coordinate with state drug controllers to collect details of TB patients and prescribers from Schedule H1 register from all the pharmacies in their respective state and send it to CTD and DCGI.
The information collected in coordination with state drug authority will help initiate follow up action with providers and patients.
On January 3, 2018, Dr Sunil Khaparde, deputy director general and head of central TB division, ministry of health and family welfare had written to all state TB officers in this regard after a meeting was held under the chairmanship of Dr Jagdish Prasad, Directorate General of Health Services (DGHS) in last week of December 2017 for coordination between DCGI and CTD to increase access of anti-TB drugs and use of Schedule H1 at private pharmacies.
The meeting aimed at increasing notification of TB patients by effective use of Schedule H1 (containing anti-TB drugs) implementation from private pharmacies and increasing access to anti-TB drugs supplied from Revised National TB Control Programme (RNTCP) to private pharmacies for TB patients.
RNTCP has taken several new initiatives such as daily regimen, universal drug susceptibility testing, active case finding in vulnerable groups, and cross reference between HIV and TB cases. The government also announced a cash incentive of Rs 500 for all TB patients as nutrition support.
The aim of RNTCP is to establish linkages with the private sector and extend free drugs, diagnostics and treatment support services to TB patients seeking care from the private sector. A big share of these public private linkages for TB can be made at the level of chemists and pharmacists from where patients purchase anti-TB medicines, prescribed by private practitioners/clinics.
In the video conference held on October 30, 2017, the secretary, health & family welfare had directed all state governments to reinforce implementation of Schedule H1 in the states and ensure availability of Schedule H1 register.
As per Schedule H1, pharmacies are required to dispense anti TB drugs on prescription of a registered medical practitioner and maintain a separate register containing the name and address of the prescriber, the name of the patient, the name of the drug and the quantity supplied and such records shall be maintained for three years and be open for inspection.
According to World Health Organisation Global TB Report 2016, India accounts for 2.8 million of the 10.4 million new TB cases globally. XDR TB constitutes 10 per cent of total MDR TB cases.
Male fertility could be at a tipping point. Last year, scientists discovered sperm counts in western countries had plummeted by 50 percent in 40 years, and while the reasons behind the decline are complex, many researchers say the phenomenon is due to men’s hormones being disrupted.
Now, one of those disruptors has come to light. In a new study, scientists show the common painkiller ibuprofen can have a negative impact on testicular health, altering hormone production and inducing a condition called compensated hypogonadism, which affects reproductive health in men.
“Our immediate concern is for the fertility of men who use these drugs for a long time,” biomedical researcher David Møbjerg Kristensen from the University of Copenhagen in Denmark told The Guardian.
“These compounds are good painkillers, but a certain amount of people in society use them without thinking of them as proper medicines.”
While previous research had already demonstrated that foetal exposure to ibuprofen and other analgesics (like aspirin and paracetamol/acetaminophen) could be harmful, less was known about its potential effects on adult men.
To find out, researchers recruited 31 male participants aged between 18 and 35, giving half of them a moderate dose (600 milligrams, equivalent to three tablets) of the drug daily for six weeks, while the other group took a placebo.
For context, up to 3,200 mg per day is considered the maximum daily adult limit by some medical sites. But even a small fraction of that dosage had a negative effect on the men after two weeks of daily use.
Within 14 days, the men taking daily ibuprofen exhibited an increase in luteinising hormones – which help regulate testosterone production – indicating the drug had impaired healthy testicular function, forcing the body to compensate by boosting testosterone levels.
While this effect wasn’t permanent, the researchers warn prolonged use of ibuprofen by men could potentially progress to more serious conditions causing low testosterone production – which might end up harming their fertility.
“[I]t is also of concern that men with compensated hypogonadism may eventually progress to overt primary hypogonadism, which is characterised by low-circulating testosterone and prevalent symptoms including reduced libido, reduced muscle mass and strength, and depressed mood and fatigue,” the team writes.
While researchers are welcoming the findings, they also say the most alarming outcomes are unlikely for most people. Also, given the results come from such a small sample, more research is definitely needed.
“Further studies are required to investigate whether this mild effect of ibuprofen could significantly impair testicular function in terms of testosterone levels, or fertility, after long term use – this study did not examine effects on fertility,” explains endocrinologist Ali Abbara from Imperial College London, who wasn’t involved in the study.
“The effects were very mild even after six weeks of regular consumption of ibuprofen, which is longer than is usually recommended in practice, so this data should not concern men who occasionally take ibuprofen for pain relief.”
As for those whose use isn’t so occasional? The results aren’t yet clear.
But given how athletes routinely use the medication to help with recurring sports injuries, experts say this is something we definitely need to stay aware of – because despite how some might abuse it, ibuprofen isn’t something that was ever intended to be taken casually.
“[T]he alarm has been raised now,” one of the team, Bernard Jégou from the Institute of Research in Environmental and Occupational Health in France told CNN.
“[I]f this serves to remind people that we are really dealing with medical drugs – not with things which are not dangerous – this would be a good thing.”
The findings are reported in Proceedings of the National Academy of Sciences.
The Central Drugs Standard Control Organisation (CDSCO) and state drug controllers have started conducting joint inspections of manufacturing facilities across the country to check the compliance levels of Schedule M as per GMP norms.
Joint inspections are aimed at streamlining uniform inspection procedures across the country related to GMP. The inspections have been closely followed with the responses drawn from the concerned manufacturers based on the checklist issued for self audit meant to assess adherence to the licensing conditions as envisaged in the Drugs and Cosmetics Act.
Drug Controller General of India Dr G N Singh said, “The joint inspections have been started and will be helpful in assessing compliance levels of the concerned manufacturers.”
The CDSCO has also been conducting risk based inspections across the country to verify GMP compliance as per the provisions stated under Schedule M of Drugs and Cosmetics Rules, 1945. It has till date concluded 185 risk based inspections in 8 phases.
These risk based inspections are based on a checklist issued for the state drug regulators to ensure that there is uniformity of inspections across all the Schedule M units in the country. CDSCO checklist and evaluation is also aimed at streamlining uniform inspection procedures across the country related to GMP.
The checklist and tool is meant to help CDSCO and state drug regulators to understand and collaborate which pharmaceutical and active pharmaceutical ingredient (API) manufacturing sites have been inspected and are found to be compliant.
Meanwhile, Maharashtra FDA is in the process of verifying compliance reports of self -audits done by around 800 manufacturers in the state.
Maharashtra FDA canceled 36 manufacturing licenses and suspended another 90 after serving 136 show cause notices (SCN) for non-compliance of D&C Rules last year. The state regulator had conducted 837 inspections over the past 6 months for the period from April 2017 to October 2017.
CDSCO has also recently proposed towards making stability tests compulsory for all drugs, including active pharmaceutical ingredients (APIs). An advisory letter has already been sent to the state drug controllers and a notification amending the rules is likely to come soon, according to a senior CDSCO official.
Once the rules take effect, pharma companies will have to subject their products to quality tests to make sure that drugs do not lose their potency and the expiry dates printed on the packaging are based on the test results.
Alzheimer’s disease is a devastating brain illness that affects an estimated 47 million people worldwide. It is the most common cause of dementia in the Western world.
Despite this, there are currently no treatments that are effective in curing Alzheimer’s disease or preventing its relentless progression.
Alzheimer’s disease is caused by the build-up of two abnormal proteins, beta-amyloid and tau. Tau is particularly important because it causes neurons and their connections to die, preventing brain regions from communicating with each other normally.
In the majority of cases, tau pathology first appears in the memory centres of the brain, known as the entorhinal cortex and hippocampal formation. This has been shown to occur many years before patients have any symptoms of disease.
Over time, tau begins to appear in increasing quantities throughout the brain.
This causes the characteristic progression of symptoms in Alzheimer’s diseases, where initial memory loss is followed by more widespread changes in thinking and behaviour that lead to a loss of independence. How this occurs has been controversial.
In our study, published in Brain, we provide the first evidence from humans that tau spreads between connected neurons.
This is an important step, because stopping this spread at an early stage might prevent or freeze the symptoms of Alzheimer’s disease.
This idea, called “transneuronal spread”, has been proposed before and is supported by studies in mice. If abnormal tau is injected into a healthy mouse brain, it quickly spreads and causes the mice to manifest dementia symptoms.
However, it had not previously been shown that this same process occurs in humans. The evidence from mouse studies was controversial, as the amount of tau injected was relatively high, and disease progression occurred much more rapidly than it does in humans.
In our study, we combined two advanced brain imaging techniques. The first, positron emission tomography (PET), allows us to scan the brain for the presence of specific molecules.
With this, we were able to directly observe the abnormal tau in living patients, to see exactly how much of it was present in each part of the brain.
The second, functional magnetic resonance imaging (fMRI), measures blood flow in the brain in real time. This allowed us to observe the activity produced by brain regions communicating with each other.
For the first time, by scanning the same people with both methods, we were able to directly relate the connections of the brain to the distribution of abnormal tau in living humans with Alzheimer’s disease.
We used a mathematical technique called “graph analysis” to analyse brain connectivity. This technique involved splitting the brain up into 598 regions of equal size.
We then treated the connectivity between regions like a social network, assessing factors such as the number of contacts a brain region had, how many “friendship” groups it took part in, and how many of a brain region’s contacts were also contacts of each other.
In a flu epidemic, people with a large number of social contacts are most likely to become infected and then to pass the infection on to others.
Similarly, the transneuronal spread hypothesis predicts that strongly connected brain regions will accrue most tau. This is what we observed. This relationship was present within each brain network individually, as well as across the whole brain.
We were also able to exclude potential alternative explanations for the appearance of tau throughout the brain.
It had previously been suggested that tau might appear at brain regions that were vulnerable because of high metabolic demand or a lack of support from their neighbours.
While it is possible that these factors are important in neuronal death, our observations were not consistent with them being the primary drivers of the initial accumulation of abnormal tau.
In addition, by looking at patients with a range of disease severity, from mild cognitive impairment through to established Alzheimer’s disease, we were able to disentangle the causes of tau accumulation from its consequences.
We showed that increasing amounts of tau in Alzheimer’s disease caused the brain to become less connected overall, and the connections that remained became increasingly random.
Finally, we contrasted the findings in Alzheimer’s disease to a rarer condition called progressive supranuclear palsy (PSP), which affects approximately three in every 100,000 people.
This condition is also caused by tau, but it remains confined to the base of the brain. We demonstrated that in PSP the evidence did not support transneuronal spread.
This might be because of the different structure of abnormal tau pathology in the two diseases. In Alzheimer’s disease, tau is present in “paired helical filaments”, while in PSP it is in “straight filaments”.
We showed that as PSP progresses, direct long-range connections are preferentially damaged, meaning that information had to take a more indirect route across the brain.
This might explain why, when asked a question, patients with PSP usually respond slowly but correctly.
Overall, evidence of transneuronal spread in humans with Alzheimer’s disease provides proof of concept for exciting new treatment strategies to lock up tau pathology before it can cause significant damage.
Indian pharmaceutical companies and their subsidiaries received 304 final ANDA approvals from US FDA during 2017 as compared to 201 ANDA approvals in the previous year. The US FDA approved total 846 ANDA during 2017 which remained highest during last decade. Indian companies with enhanced R&D investments during last couple of years, managed to secured almost 36 per cent of total approvals by US FDA. Further, US FDA approved 171 tentative approvals and out of this Indian companies grab 61 tentative approvals in 2017. Higher rate of approvals for Indian companies will translate into higher revenues in near future.
During the last decade viz., 2008-2017, US FDA approved total 5,020 ANDAs and 1184 tentative approvals. Out of this, Indian companies grab 1,695 ANDA approvals and 455 tentative approvals. The average rate of securing approvals by Indian pharma companies worked out to almost 34 per cent for last decade. Thus, Indian pharma companies received healthy product approvals from highly regulated US body which will turned into higher export earnings.
Among the Indian pharma companies, Cadila Healthcare and its US based subsidiary remained on top in securing highest number of approvals during 2017. Cadila Healthcare and its US based subsidiary Zydus Pharmaceutical USA, Inc, have secured approvals for 71 ANDAs during 2017 and followed by Aurobindo Pharma (51), Sun Pharma & Taro Pharma (21) Glenmark Pharmaceutical (18), Gland Pharma (16), Alkem Laboratories (15), Macleods Pharma (15), Lupin (13), and Cipla and Dr Reddy’s Laboratories 10 each. Further, Strides Shashun and Alembic Pharma received 9 ANDA approvals from US FDA during 2017.
Though the Indian pharma majors have faced quality problems raised by US FDA and getting warning letters as well as ban on exports, Indian companies have taken steps to overcome the same and invested higher funds in research activities. Higher investment in R&D helped them to secure higher number of product approvals. The US market is key growth driver for Indian pharma companies and actions or ban on Indian products may impact working and share price movements. Several Indian pharma giants suffered heavily during 2017 due to the US FDA actions.
Cadila Healthcare research activities is spread across five broad segments viz. NCE, biologics, vaccines, APIs and formulations development. Focused areas of NCE research include cardio-metmabolic disorder, inflamation, pain and oncology. It initiated phase II clinical trials of Saroglitazar Magnesium (Lipaglyn) in US for two indications viz. Non-alcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. Its biologics R&D initiative includes 18 biosimilars and 7 novel products as at the end of March 2017. It completed phase III clinical trials for one more monoclonal antibody (mAb).
Apart from ANDA approvals, Cadila is also developing vaccine portfolio and it received marketing authorization for seven additional vaccines from DCGI. The company has setup 32 manufacturing facilities across the globe, 27 of them located in India, 3 in the US, and one each in Brazil and Germany. Out of total 32 facilities, 11 have been inspected by the US FDA.
Aurobindo Pharma’s product portfolio is spread over 7 major therapeutic/product areas encompassing antibotics, anti-retrovirals, CVS, CNS, gastroenterologicals, anti-allegies and anti diabetics, supported by R&D setup. It received 51 final ANDA approvals during 2017. Recently it received final approval for manufacture and market fondaparinux sodium injections. This is 52nd ANDA to be approved out of Unit IV formulation facility in Hyderabad. It has a total of 350 ANDA final approvals from US FDA and 37 tentative approvals. Its subsidiary Aurolife Pharma LLC received 17 approvals.
Glenmark Pharma is currently marketing 126 generic products in US market. It has 61 applications pending in various stages of the approval process with the US FDA, of which 28 are Paragraph IV applications. During the second quarter ended September 2017, it received eight final approvals taking the tally to 13 final approvals for the first half of this financial year. It filed three ANDA applications with US FDA and plans to file an additional seven applications in the forthcoming quarter. It also filed 2 US DMFs and 1 EU CEP and completed several other regulatory filings in other key markets including Brazil and South Korea.
During the September 2017 quarter, Glenmark entered into a development, license, manufacture and commercial supply agreement with Cyndea Pharma SL. Under this agreement, Glenmark received exclusive rights to the US and Canada markets for these soft-gelatin formulations in exchange for sharing development costs and profits from future sales.
Lupin’s R&D expenditure declined to Rs.973 crore during the first half ended September 2017 from Rs.1,071 crore in the corresponding period of last year. Its cumulative ANDA filings with the US FDA stood at 377 as of September 30, 2017 and it received 225 approvals upto first half. It now has 49 First-to-Files filings including 25 exclusive FTF opportunities. Cumulative DMF filings stands at 188 as of end of September.
During the quarter, on the R&D side, we made significant progress. GBR 830, an investigation, first-in-class, anti-OX40 monoclonal antibody, reported positive data in a phase 2a for the treatment of patients with Atopic Dermatitis. After reporting positive phase 3 data on GSP 301, we continue to make progress towards filing the NDA in 2018. This will be the first NDA filed by the organization.”
Alkem Laboratories R&D expenditure for the first half ended September 2017 reached at Rs.160 crore, or 5.1 per cent of total revenue from operations. The company is strengthening its R&D activities to strengthen product pipeline. Its US sales increased to Rs.304 crore during first half of 2017-18. The company received 15 final ANDA approvals from US FDA in 2017.
Wockhardt’s R&D expenditure was at Rs.149 crore during the first half ended September 2017 and it received 5 ANDA approvals in 2017. Its net sales declined sharply by 11.3 per cent to Rs.1,913 crore from Rs.2,156 crore. International business contributed 61 per cent of the total revenues in the first half. Its US sales stands at 16 per cent of its global revenue.
Besides above pharm companies, Jubilant Lifesciences, Ajanta Pharma, Micro Labs, Unichem Laboratories, Torrent Pharma, Natco Pharma, Orchid Pharma, Panacea Biotic, Granules India, Hetero Labs, Intas Pharma, Marksans Pharma and Vintage Pharma also received approvals from US FDA in 2017.