Is there a pharma boom going on in India?

Stock market fluctuations are too unreliable of an approach to assess an entire industrial sector. Wild speculations apart, something tangible needs to underpin any boom. While Indian Pharma doesn't have upcoming blockbusters, several trends augur its healthy growth.

Indian Pharma: Essentially High Volume-Low Value Global Supplier Of Generics

The world's 3rd largest pharmaceutical industry by volume (10% of global production) but only 14th by value (1.5% of global value) suggests Indian Pharma is a high-volume, low-value proposition (1).

A highly fragmented industry with ~10000 manufacturers, though only ~250 are large-scale, generics dominate Indian Pharma (2), contributing no less than 40% of the US generic drug import for example.

US FDA drug approvals reveal Indian Pharma doesn't have a strong presence in the US new drug market. Of the 96 new drugs it approved in 2013, only 2 were from Indian companies, Lupin's Suprax (active ingredient Cefuroxime) and Alembic's extended release form of anti-depressant desvenlafaxine (3). Thus, a boom can't be justified on hopes of extremely big paydays down the road from expensive new blockbusters selling on drug markets like the USA or the EU. That's simply not Indian Pharma's track record nor is such a US-like process even likely in India, where the government deliberately intervenes with powerful instruments like price controls and compulsory licenses. Through the latter mechanism, if the Indian government deems an originating firm’s listing price unaffordable, it can force them to license their technology to a generic competitor, an extremely strong countervailing force that, though seldom used, hangs like a Damocles sword over the pricing decisions originator firms make when trying to sell their products in India (2, 4), a situation utterly unlike the rampant drug price gouging that's today the norm in the US. This is why drugs in India are among the cheapest in the world (2). Also why Indian Pharma depends on drug volume not price for its profits.

Indian Pharma: Nearing An Inevitable Fork In The Road, Will It Be Super Generics or Biosimilars Next

On the plus side, Indian pharma has built up an enviable infrastructure, with the largest number of US FDA compliant API (Active Pharmaceutical Ingredient) manufacturing plants outside the US (>262), ~1400 WHO GMP-approved plants and 252 European Directorate of Quality Medicines (EDQM) approved plants (1). This capacity has made Indian Pharma a global leader in generics, supplying anti-HIV drugs widely across Africa, Asia, Latin America for example.

Long specializing in generics, Indian pharma faces a major fork in the road in terms of how to expand and diversify in an extremely rapidly changing global pharma landscape. In the ongoing Patent cliff, i.e., patent expiration of blockbuster drugs coming off of patent since 2011 continuing through to 2019, bulk of the patent loss on traditional pharmaceutical drugs has already occurred. Far fewer are expected after 2017. Thus the generics market can only remain a high volume-low value proposition for Indian Pharma.

To gain value, Indian Pharma has to climb the value chain. Developing new drugs all by itself is an extremely costly proposition with very high regulatory burden. New drug development never having been its expertise, options that best leverage Indian Pharma's existing expertise and capability are super generics and biosimilars.

Super Generics represent an incremental innovation to Indian pharma's already well-established generics capability. Though they entail greater regulatory burden, Indian Pharma's making steady inroads into this space (see below from 3, 5).

As generics are to patented drugs so Biosimilar are to biologics (6). Indian Pharma is a relative newcomer in the biologics and biosimilars arena. Making biosimilars, while much more arduous and expensive compared to generics (see below from 7), may yield greater long-term payoff in terms of expanding technological capability which could serve as a launching pad for in-house new drug development down the road.

The ongoing Patent cliff on biologicals (3, see below from 7) is thus a net opportunity for Indian Pharma to enter the biosimilars sector.

Biocon was one of the early entrants, getting approval for its biosimilar CANMab, a remake of Roche's Trastuzumab (Herceptin), a breast cancer drug (8).

Indian Pharma: Steadily Increasing Global Reach Through Mergers, Acquisitions & Joint Ventures

Joint ventures offer a ready-made platform for global pharma to leverage R&D capabilities of well-established Indian entities as Contract research organization (CRO), which helps to considerably reduce cost of new drug development.

In the long-term, expansion of Indian CROs can also help Indian Pharma gain the technological, managerial and regulatory know-how necessary for new drug development, something they currently lack.

Indian Pharma's also been steadily increasing its presence in other countries through acquisitions. A 2016 study reported that 67 Indian companies valued at >US $6 billion made 191 acquisitions across 33 countries from 2000 to 2012 (see tables below from 9, 10).

Indian Pharma: Serious Teething Problems With Clinical Trials

Vast genetic diversity, large 'treatment-naive' population, ~30% urban dwellers with >67 million living in India's 6 largest cities alone plus cost of conducting a clinical trial in India is < 50% of that in the US, all these factors make India an attractive destination for conducting clinical trials. However recent speed-bumps in the form of serious lack of oversight in clinical trial recruitment and informed consent processes (11, 12, 13) have chilled Indian clinical trial activity. A lessons learned mind-set on the part of global pharma and its local regulators and clinical trial partners would help resume trial activity.

Indian Pharma: Dwindling Opportunities For Contract Research For API (Active Pharmaceutical Ingredient) Manufacturing For Europe & USA

Along with China, India leads in API manufacture (see below from 14).

In their efforts to reduce manufacturing costs in Europe and USA, in recent years their Big Pharma increasingly off-loaded API manufacturing to cheaper sites located in places like India. This meant increased scrutiny from foreign regulatory authorities like the US FDA. Indian Pharma leads the pack in number of US FDA warning letters (15). While these setbacks can be and indeed are being interpreted several ways, a pragmatic interpretation would be to see them as a steep but necessary learning curve for Indian Pharma to effectively compete in supplying essential drugs to the US and the EU. Indian Pharma got here by becoming an expert mass manufacturer of API. However, shoring up manufacturing to meet their more stringent regulatory standards is beneficial in the long-term as it improves Indian Pharma's QA/QC, data integrity and compliance standards. High profile warning letters are also beneficial in highlighting a glaring shortcoming in the Indian Pharma regulatory landscape, namely long-standing, tremendous shortage of well-trained and qualified drug inspectors (16, 17), something the Drug Controller General of India, G.N. Singh himself conceded in Jan 2014 is a situation that desperately needs improving (18).

'You cannot equate the Indian regulator with the US one. We are still evolving and it will take us at least 10 years to reach that level. We do not have resources and infrastructure equivalent to those of US FDA. We have a total staff of 650, compared with US FDA's 13,000. Look at the size of our manufacturing industry. The Indian industry is currently supplying generics to over 214 countries.

Also, as a national regulator, the steps that we are taking are voluntary. Manufacturing compliance and quality assurance is a state subject.'

To add to Indian Pharma's woes,

• On 16th July, 2015, the European Commission directed all its member states to suspend national marketing authorization of 700 generic drugs tested and approved by GVK Biosciences (19).
• An early 2016 decision by the US government's made it mandatory for APIs to be manufactured locally for government procurement. According to Live Mint (20), currently ~88% (9 out of 10) of prescriptions dispensed in the US are for generics. India and China are the largest API suppliers to the US. Of the US $2 to 3 billion worth of API that India exports to the US, ~40% is for government purchase so this decision will definitely hit Indian Pharma exports and companies with holdings or subsidiaries in the US.

Thus, Indian Pharma outlook looks bright if it leverages its proven generics expertise into expanding into super generics and biosimilars. Becoming a preferred destination as a clinical trials site and an essential cog in the drug supply chain to the US and the EU, however, need more work in improving its compliance and manufacturing to match their more rigorous standards.

Bibliography

1. Pharma Industry Promotion | Department of Pharmaceuticals

2. http://www.pacificbridgemedical....

3. Suri, F. K., and A. Banerji. "Super Generics—First Step of Indian Pharmaceutical Industry in the Innovative Space in US Market." Journal of Health Management (2016): 0972063415625566.

4. Duggan, Mark, Craig Garthwaite, and Aparajita Goyal. "The market impacts of pharmaceutical product patents in developing countries: Evidence from India." The American Economic Review 106.1 (2016): 99-135. https://openknowledge.worldbank....

5. Stegemann, Sven, et al. "Improved therapeutic entities derived from known generics as an unexplored source of innovative drug products." European Journal of Pharmaceutical Sciences 44.4 (2011): 447-454. https://www.researchgate.net/pro...

6. http://www2.deloitte.com/content...

7. Daubenfeld, Thorsten, et al. "Practitioner’s Section." Journal of Business Chemistry 13.1 (2016): 33. http://www.businesschemistry.org...

8. The Hindu, Jan 18, 2014. Biocon launches cheaper breast cancer drug

9. Trehan, A., Gaikwad, A. Indian Pharma Industry: Trends, Predictions and Challenges. Asia-Pacific Biotech News, 2014: 18: 27-44. Asia Pacific Biotech News - PR NEWSWIRE

10. Jayanthi, Bhargavi, S. N. V. Sivakumar, and Arunima Haldar. "Cross-border Acquisitions and Host Country Determinants: Evidence from Indian Pharmaceutical Companies." Global Business Review 17.3 (2016): 684-69.

11. Tirumalai Kamala's answer to Should we have an international forum to resolve clinical trial mishaps?

12. Tirumalai Kamala's answer to Is it true that Bill Gates faced trial in India for illegally testing tribal children with vaccines?

13. Tirumalai Kamala's answer to Do western drug companies test more dangerous drugs on the poor in India, and should they be held accountable?

14. CHEManager Europe, April 2012. Will API Manufacturing Move out of India and China? http://thomsonreuters.com/conten...

15. Business Standard, Aneesh Phadnis, May 5, 2016. Indian drug units violate most US pharma regulators' rules

16. Kadam, Abhay B., et al. "Correcting India’s chronic shortage of drug inspectors to ensure the production and distribution of safe, high-quality medicines." (2016). http://www.allysonpollock.com/wp...

17. A report on fixing India's broken drug regulatory framework. Dinesh S. Thakur, Prashant Reddy T. June 4, 2016. http://spicyip.com/wp-content/up...

18. Business Standard, Sushmi Dey, Jan 30, 2014. If I follow US standards, I will have to shut almost all drug facilities: G N Singh

19. European Medicines Agency - Human medicines - GVK Biosciences

20. Live Mint, Reghu Balakrishnan, Shine Jacob, Feb 6, 2016. No major impact on API import ban in US

https://www.quora.com/Is-there-a-pharma-boom-going-on-in-India/answer/Tirumalai-Kamala

Is Diet Coke (or other diet sodas) good or bad for dieting and weight loss? Does diet soda cause people to gain weight? If so, why?

Sweet taste without the calories sounds like a perfect example of no pain, all gain but unfortunately cumulative data suggests otherwise. A poster child for unintended consequences, diet soda (Diet drink) typically contains a type of non-caloric artificial sweetener, Sugar substitute called Aspartame, e.g., NutraSweet or Equal (sweetener). Unintended consequences in the form of not just weight gain but also increased risk of Cardiovascular disease, Diabetes mellitus type 2, Hypertension, Metabolic syndrome, all vigorously disputed of course (see some examples in references 1, 2), which brings us to the glaring caveat we need to keep front and center when considering the science about artificial sweeteners. Historically the food and beverage industry has funded nutrition research so substantially, the ensuing entrenched conflict of interest renders the phrase 'nutrition science' an oxymoron (3).

North America currently leads in sales and consumption of diet beverages (see below from 4).

Artificial sweetener consumption patterns tend to change rapidly in response to widespread perception of harm attendant to one type of artificial sweetener or another. US artificial sweetener consumption for example moved from cyclamate in the 1960s to Saccharin, e.g., Sweet'n Low, to aspartame which reigned supreme for several decades until being upstaged in the 2010s by Sucralose, e.g., Splenda, mainly because it's highly stable in food (5) while Acesulfame potassium (Ace-K), e.g., Sunett, Sweet & Safe, Sweet One, is also increasing in use. Pepsi embodies such rapid change. In 2015 it changed its US Diet Pepsi formulation replacing aspartame with sucralose and Ace-K (6) but for reasons best known to itself announced in 2016 it was bringing aspartame back while also retaining the reformulated products (7). Meantime so-called natural sweeteners like Stevia aka Truvia are also rapidly increasing in prevalence (4).

'If you can avoid taking in more food, does diet soda still somehow make you gain weight?'

Weight gain without increased food intake is in fact a strikingly consistent observation in many animal model studies on artificial sweeteners (8, 9, 10). How does this happen? Problem with understanding how these artificial sweeteners affect human metabolism and health long-term is each artificial sweetener is different in chemistry, biology and pharmacokinetics (11, 12, 13, 14, see below from 4, 15). Obviously each will induce different metabolic and health effects.

For long, uncertainty dogged epidemiological studies on artificial sweeteners. Do they cause cancer or not? Do they increase risk of diabetes and/or obesity or not? Do they play a role in metabolic syndrome or not? And so on. Given the big bucks riding on ensuring people continued to guzzle at least diet soda even as the tide turned against sodas in general (16), unsurprising really that much of this data is conflicting, mostly due to avoidable study design flaws such as assessing artificial sweetener consumption in conditions far removed from how they're consumed in real life, which is as part of a typical unhealthy 'Western' diet replete in highly processed food and as part of a highly sedentary lifestyle. Few studies included children or elderly or minorities or low income, few examined long-term/chronic/habitual artificial sweetener consumption.

In other words, vast chasm between such studies and real life artificial sweetener consumption patterns. Most importantly, since different artificial sweeteners are used in different processed foods and drinks and since studies rarely address a single artificial sweetener specifically, we essentially don't understand how each artificial sweetener influences metabolism and health long-term (17).

The few studies such as the San Antonio Heart (18) and Longitudinal Study of Aging (19) that examined elderly and minorities long-term (7 to 9 years follow-up) found substantial weight and waist circumference gain with artificial sweetener consumption (in soda, coffee or tea), even without increased food intake, which echoes animal model studies. Increased abdominal fat is of course now a well-known risk factor for cardiovascular disease and type II diabetes.

How to make at least minimal sense of the tower of Babel that is artificial sweetener-related data? Same way as other prickly scientific issues, by looking at conclusions of systematic reviews and Meta-analysis. However, given the entrenched practice of the food and beverage industry funding a massive amount of nutrition research, not meta-analyses by just anyone but rather by those not funded by them. Since Publication bias, i.e., overweening dominance of studies with statistically significant results, is widespread, such reviews and analyses will naturally also be hobbled by the same drawback. However, since they use a set of objective criteria to assess a wide variety of individual studies ranging from cross-sectional to interventional to observational to prospective to randomized, placebo-controlled trials, they're still far more robust and objective than individual studies claiming to find in favor of one or other hypothesis.

• One such review (20) was conducted by federally funded Purdue University researcher Susan E. Swithers. It assessed differences between diet soda non-consumers and consumers among >450000 participants across 14 independent Prospective cohort study, including the San Antonio Heart Study (18), with an average 16-year followup. It concluded that regardless of baseline weight in the two groups, regardless naturally or artificially sweetened, soda consumption increased risk of not just weight gain but also cardiovascular disease, hypertension, metabolic syndrome and type II diabetes (20). Typically, bad news about artificially sweetened stuff is discredited by arguing overweight people tend to choose it in the first place trying to lose weight, i.e., by arguing reverse causality (21). In other words, arguing drinking artificially sweetened stuff doesn't cause weight gain, rather overweight people drink it to try to lose weight. This review (20) found that not to be the case.
• Swithers concluded (20),

‘recent data from humans and rodent models have provided little support for ASB(everages) [artificially sweetened beverages] in promoting weight loss or preventing negative health outcomes such as T2D [type II diabetes], metabolic syndrome and cardiovascular event'

‘current findings suggest that caution about the overall sweetening of the diet is warranted, regardless of whether the sweetener provides energy directly or not’

• No surprise these conclusions were vigorously disputed on the grounds that (22)

'Robust scientific evidence demonstrates benefits of artificial sweeteners’

• In her authoritative rebuttal (23), Swithers points out the American Heart Association (AHA) and American Diabetes Association (ADA) themselves stated in 2012 lack of robust scientific data about artificial sweeteners (24, emphasis mine),

‘paucity of data from well-designed human trials exploring the potential role of (non-nutritive sweeteners) in achieving and maintaining a healthy body weight and minimizing cardiometabolic risk factors.’

• In other words, these products have been unleashed indiscriminately on society, making their way into thousands upon thousands of food and drinks that billions consume and yet we apparently don't know enough to conclude if they're beneficial or not. Sounds like a recipe for a slow motion disaster, which the modern-day global obesity epidemic indeed is, with both sugars and artificial sweeteners obviously playing leading roles.
• Another systematic review of 18 studies by US NIH researchers found association between consumption of artificial sweetened beverages and weight gain in children and teens (25).

Future artificial sweetener research will likely coalesce around at least 3 aspects:

1) How artificial sweeteners influence Gut flora composition and metabolism.

2) How they drive behavioral & metabolic compensation.

3) Biomarkers to identify those at highest risk of sugar/replacer-induced weight gain and/or metabolic disruption.

1) Artificial sweetener effect on Gut flora composition and metabolism.

Since most artificial sweetener studies focus on their effect on body weight, important aspects about their metabolism remain under-studied. This is because they were for long considered inert, passing through the GI tract, untouched, unused, little perturbed and little perturbing. Turns out that's not the case at all (26).

• In a mouse model study (27), maximal daily accepted doses of saccharin, sucralose and aspartame in their drinking water for five weeks induced mouse gut microbiota changes and Impaired glucose tolerance. How this happens is still not clear, especially since aspartame is fully digested to its constituent amino acids in the small intestine unlike saccharin and sucralose. Study found similar results in human volunteers as well. Since most of its experiments involved saccharin, this study's major caveat is limited relevance for diet sodas, which mostly contain aspartame. Obviously similar, larger study needs to examine aspartame effect separately.
• In a rat model study (28), aspartame exposure led to gut microbiota changes and elevated fasting glucose and reduced insulin-stimulated glucose consumption.

Caveat common to all fecal microbiota studies, not just this one: Fecal samples mostly represent distal colon microbiota. Different parts of the GI tract obviously harbor different microbial populations (29). This is especially pertinent for diet vis-a-vis weight gain since most nutrient digestion and absorption is in the small intestine, whose microbial composition is still rather a black box.

Implications of artificial sweetener-induced gut microbiota change:

• Are such changed microbiota better at nutrient harvesting? Better at driving adipose tissue energy storage?
• These would help explain weight gain even without increased food intake.
• Are they more harmful to gut's long-term health, making it more leaky, Intestinal permeability, triggering systemic inflammation?
• This would help explain the long-term harmful consequences such as metabolic syndrome and attendant increased risk of cardiovascular disease and type II diabetes.

2) Hypothesis: artificial sweeteners drive behavioral & metabolic compensation

Since the 1990s, Purdue University researcher Susan E. Swithers has pioneered animal model studies to explore how artificial sweeteners could uncouple sweet tastes from their metabolic consequences and thus distort ability to predict the latter. In other words, artificial sweeteners may alter how the brain processes reward for sweet taste. Her reviews refer to several such experimental studies (30, 31) by hers and other groups.

3) Biomarkers to identify those at highest risk of sugar/replacer-induced weight gain and/or metabolic disruption

Biomarker are measurable, often quantifiable biological indicators of some condition.

As with anything diet-related, some seem to gain weight no matter what or how much they eat, some don't while most of the rest fall somewhere in between. How to proactively identify those at highest risk of weight gain and/or metabolic disruption from artificial sweeteners? The US Scientific Report of the 2015 Dietary Guidelines Advisory Committee advises (32),

'future experimental studies should examine the relationship between ASSD [artificially sweetened soft drinks] and biomarkers of insulin resistance and other diabetes biomarkers'

Only when we have data from such studies will we be able to delve into genetic markers, specific gut microbiota composition, etc., that differentiate those most at risk from the harmful effects of artificial sweeteners, something we have no clue of at present.

Bibliography

1. Stevens, Haley Curtis. "Diabetes and diet beverage study has serious limitations." The American journal of clinical nutrition 98.1 (2013): 248-249. Diabetes and diet beverage study has serious limitations

2. La Vecchia, Carlo. "Artificially and sugar-sweetened beverages and incident type 2 diabetes." The American journal of clinical nutrition 98.1 (2013): 249-250. Artificially and sugar-sweetened beverages and incident type 2 diabetes

3. Vox, Julia Belluz, August 16, 2016. Why (almost) everything you know about food is wrong

4. Popkin, Barry M., and Corinna Hawkes. "Sweetening of the global diet, particularly beverages: patterns, trends, and policy responses." The Lancet Diabetes & Endocrinology 4.2 (2016): 174-186.

5. Sylvetsky, Allison C., and Kristina I. Rother. "Trends in the consumption of low-calorie sweeteners." Physiology & behavior (2016).

6. The Guardian, Suzi Gage, 28 April, 2015. Diet Pepsi has dropped aspartame in the US, so why not anywhere else?

7. Fortune, John Kell, June 27, 2016. Diet Pepsi with aspartame is making a comeback

8. Abou-Donia, Mohamed B., et al. "Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats." Journal of Toxicology and Environmental Health, Part A 71.21 (2008): 1415-1429. https://www.researchgate.net/pro...

9. Polyák, Éva, et al. "Effects of artificial sweeteners on body weight, food and drink intake." Acta Physiologica Hungarica 97.4 (2010): 401-407. https://www.researchgate.net/pro...

10. de Matos Feijó, Fernanda, et al. "Saccharin and aspartame, compared with sucrose, induce greater weight gain in adult Wistar rats, at similar total caloric intake levels." Appetite 60 (2013): 203-207. https://www.researchgate.net/pro...

11. Byard, J. L., and L. Golberg. "The metabolism of saccharin in laboratory animals." Food and cosmetics toxicology 11.3 (1973): 391-402.

12. Ranney, R. E., et al. "Comparative metabolism of aspartame in experimental animals and humans." Journal of Toxicology and Environmental Health, Part A Current Issues 2.2 (1976): 441-451.

13. Arnold, D. L., D. Krewski, and I. C. Munro. "Saccharin: a toxicological and historical perspective." Toxicology 27.3 (1983): 179-256.

14. Roberts, A., et al. "Sucralose metabolism and pharmacokinetics in man." Food and chemical toxicology 38 (2000): 31-41.

15. Logue, C., et al. "The potential application of a biomarker approach for the investigation of low-calorie sweetener exposure." Proceedings of the Nutrition Society 75.02 (2016): 216-225.

16. The New York Times, Margot Sanger-Katz, October 2, 2015. The Decline of ‘Big Soda’

17. Wiebe, Natasha, et al. "A systematic review on the effect of sweeteners on glycemic response and clinically relevant outcomes." BMC medicine 9.1 (2011): 1. BMC Medicine

18. Fowler, Sharon P., et al. "Fueling the obesity epidemic? Artificially sweetened beverage use and long‐term weight gain." Obesity 16.8 (2008): 1894-1900. https://www.researchgate.net/pro...

19. Fowler, Sharon PG, Ken Williams, and Helen P. Hazuda. "Diet soda intake is associated with long‐term increases in waist circumference in a biethnic cohort of older adults: The San Antonio longitudinal study of aging." Journal of the American Geriatrics Society 63.4 (2015): 708-715. http://www.nutritiondesseniors.f...

20. Swithers, Susan E. "Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements." Trends in Endocrinology & Metabolism 24.9 (2013): 431-441. http://citeseerx.ist.psu.edu/vie...

21. Drewnowski, A., and C. D. Rehm. "The use of low-calorie sweeteners is associated with self-reported prior intent to lose weight in a representative sample of US adults." Nutrition & diabetes 6.3 (2016): e202. http://www.nature.com/nutd/journ...

22. Johnston, C. A., and J. P. Foreyt. "Robust scientific evidence demonstrates benefits of artificial sweeteners." Trends in endocrinology and metabolism: TEM 25.1 (2014): 1.

23. Swithers, Susan E. "A paucity of data, not robust scientific evidence: a response to Johnston and Foreyt." Trends in Endocrinology & Metabolism 25.1 (2014): 2-4.

24. Gardner, Christopher, et al. "Nonnutritive sweeteners: current use and health perspectives a scientific statement from the American heart association and the American diabetes association." Diabetes care 35.8 (2012): 1798-1808. http://care.diabetesjournals.org...

25. Brown, Rebecca J., Mary Ann De Banate, and Kristina I. Rother. "Artificial sweeteners: a systematic review of metabolic effects in youth." International Journal of Pediatric Obesity 5.4 (2010): 305–312. http://seriecientifica.org/sites...

26. Nettleton, Jodi E., Raylene A. Reimer, and Jane Shearer. "Reshaping the gut microbiota: Impact of low calorie sweeteners and the link to insulin resistance?." Physiology & behavior (2016).

27. Suez, Jotham, et al. "Artificial sweeteners induce glucose intolerance by altering the gut microbiota." Nature 514.7521 (2014): 181-186. https://www.researchgate.net/pro...

28. Palmnäs, Marie SA, et al. "Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat." PLoS One 9.10 (2014): e109841. http://journals.plos.org/plosone...

29. Lichtman, Joshua S., et al. "The effect of microbial colonization on the host proteome varies by gastrointestinal location." The ISME journal (2015).

30. Swithers, Susan E. "Artificial sweeteners are not the answer to childhood obesity." Appetite 93 (2015): 85-90. http://www1.appstate.edu/~kms/cl...

31. Swithers, Susan E. "Not-so-healthy sugar substitutes?." Current opinion in behavioral sciences 9 (2016): 106-110. Not-so-healthy sugar substitutes?

32. https://health.gov/dietaryguidel...

https://www.quora.com/Is-Diet-Coke-or-other-diet-sodas-good-or-bad-for-dieting-and-weight-loss-Does-diet-soda-cause-people-to-gain-weight-If-so-why/answer/Tirumalai-Kamala

How proven a technique is cupping for sports recovery?

Not proven at all. Most cupping benefits are likely Placebo effects.

History Of Cupping: A Massage Therapeutic Supposed to Restore Balance To The Body's Humors As Per The Ancient Medical Theory Of Humorism Popularized By Galen

Cupping is an ancient vacuum pressure technique. Its reports stretch back thousands of years from sources as varied as Egypt, China, Iran to Arabia (where it's called Hijama) to Europe, Korea and even Mongolia. Continuing to exist outside mainstream medicine the world over, high profile clients like Jennifer Aniston, Gwyneth Paltrow, Lena Dunham and now Michael Phelps raised its public profile in the 2000s and beyond. Yet cupping's benefits lack rigorous scientific evidence. This may be because over the centuries, as scientific medicine took root, cupping got relegated to the sidelines, practiced not by licensed physicians but by support staff and of course quacks. Consider late medieval England for example. Though hardly the bastion of rational, evidence-based medicine, even this era considered cupping an alternative, the purview not of physicians but of barber-surgeons, who apart from being licensed to cut hair, were allowed to perform minor superficial interventions such as cupping and leeching (1).

Cupping got its start from the ancient medical theory of the four humors, blood, phlegm, black and yellow bile. The theory gave each humor two qualities. Blood was hot and wet, phlegm was cold and wet, black bile was cold and dry, and yellow bile was hot and dry (1). According to medieval European medicine, cupping-generated vacuum was supposed to extract 'vicious' humor, i.e., humor that was in imbalance (see below from 2). Obviously they didn't know that blood circulates through the pumping action of the heart, which discredits the notion of balance between different bodily humors controlling health.

However, if cupping does provide some health benefits especially for musculoskeletal diseases, the critical knowledge gap is not knowing how. Improve blood flow? Lymph flow? Modulate nerve physiology? One or all of the above? One more important than the rest? Not currently known.

Problems With Cupping

I. Cupping Lacks Rigorous, Scientific Studies, & Standardized Training & Credentialing

• Lacks rigorous, well-controlled studies on large numbers of subjects, i.e., studies with sufficient statistical power to allow inferences about mechanism of action. Since 2000, hundreds of studies including randomized clinical trials have examined cupping's effects on problems ranging from local (chronic muscle pain, fibromyalgia, herpes zoster) to systemic issues (blood pressure). However, being poorly designed, i.e., lacking rigorous controls or sufficient numbers or failing to assess adverse outcomes, most of them add little value so conclusive data's still missing.
• Since a sham wet cupping technique doesn't exist (3), an additional technical limitation is being unable to blind the study. In other words, even in a randomized clinical trial, those getting wet cupping know. This can introduce Placebo effects.
• Lack of systematic, formal, standardized training and credentialing. In many countries cupping doesn't require a medical degree or even a license. Often quacks with neither knowledge of medicine nor safe, aseptic techniques perform cupping. No surprise then that burns and infections can ensue. With the Chinese government introducing guidelines in 2010 to standardize cupping therapy across China (4), maybe at least safety will improve.

II. Cupping’s Lack Of Standardized Training & Credentialing Creates Unnecessary Risk

• Examining six databases on English language reports between 2000 and 2011, an analysis of adverse events following cupping found 10 ranging from mild (keloid scarring, burns and bullae) to more serious (acquired hemophilia A, stroke, factitious panniculitis, reversible cardiac hypertrophy and iron deficiency anemia) (5).
• Another systematic review of scientific databases between 2000 and 2016 found a total of 979 cupping studies. Discarding the majority because of various flaws, it ended up reviewing only 25 (~2.6%; 6 randomized clinical trials, 16 single case reports, 3 case series). It found adverse events related to dry cupping in 15 studies and in 8 to wet cupping (6). Scars and burns were most frequent (see below from 6).

Bibliography

1. Lindemann, Mary. Medicine and society in early modern Europe. Cambridge University Press, 1999.

2. A History Of Medicine. Dr. Jenny Sutcliffe, Nancy Duin. Morgan Samuels Editions, 1992. http://global-help.org/publicati...

3. Aleyeidi, Nouran A., et al. "Effects of wet-cupping on blood pressure in hypertensive patients: a randomized controlled trial." Journal of integrative medicine 13.6 (2015): 391-399. http://www.jcimjournal.com/artic...

4. Gao, S. Z., and B. Liu. "Study on standardization of cupping technique: elucidation on the establishment of the National Standard Standardized Manipulation of Acupuncture and Moxibustion, Part V, Cupping." Zhongguo zhen jiu= Chinese acupuncture & moxibustion 30.2 (2010): 157.

5. Xu, Shifen, et al. "Adverse events of acupuncture: a systematic review of case reports." Evidence-Based Complementary and Alternative Medicine 2013 (2013). http://downloads.hindawi.com/jou...

6. Al-Bedah, Abdullah Mohammad, et al. "Safety of Cupping Therapy in Studies Conducted in Twenty One Century: A Review of Literature." https://www.researchgate.net/pro...

https://www.quora.com/How-proven-a-technique-is-cupping-for-sports-recovery/answer/Tirumalai-Kamala

Is it true that only 50% of stage 3 clinical drug trials succeed?

Most drug candidates these days do fail at a late stage of the drug development process.

In 2011, Pammolli et al examined a large global database of R&D projects on >28000 compounds investigated from 1990 to 2004 (1). They found a clear trend of increasing attrition rates across all stages of the drug development process including an increase to >50% at Phase III by 2004 (see below from 1).

In 2012, Mestre-Ferrandiz et al performed a meta-analysis of 11 studies from 1979 to 2011 that analyzed the A-to-Z process for new drugs (2). They estimated probability of Phase III success ranges from 50 to 71%, i.e., Phase III failures ranging from 29 to 50%.

In 2013, a group of Boston Consulting Group analysts examined the 2002 to 2011 record of 842 individual molecules with known full development outcomes. They found 205, i.e., 24.3%, gained regulatory approval while the remaining 637, i.e., 75.7%, failed in Phase II or later (3). Their analysis cuts right across the BioPharma landscape, covering small (<$200 million/year on R&D), medium ($200 million to 1 billion) and large (>$1 billion) companies, both private and public, and located not just in the US but also in the EU and the rest of the world. In their analysis, the factors that correlated most with drug development success were (see below from 3).

• Scientific judgment or 'acumen' in terms of shutting projects down early, rather than late.
• Solid track record of the company's R&D in terms of publications and patents per US dollar of R&D expenditure, and citation records (# of times papers were cited by others).

• A 2012 study by Pfizer also found scientific judgment / 'acumen' to be the most critical quality. Their analysis found that 2/3rd of the company's Phase I candidates, 'assets', were advanced down the pipeline for further development even when data was already available that they would likely fail (4).
• A 2014 AstraZeneca analysis of the decision-making about their drug pipeline concluded that the 'right culture' was crucial for effective decision-making, i.e., which candidates to advance and which to terminate early (5).

Thus, several studies have now not only pointed out increasing late stage failures for new drugs but also suggest part of the problem is too many poor drug candidates are advancing to later stages, i.e., failing late rather than early. It also takes ever longer for a drug candidate to advance down the pipeline, typically ~48 months and ~US $42 million to get from selection to Phase II (2, 6). Yet barring a rare report here and there like Eli Lilly and Company's Chorus (7), which claims to have shaved this time down to ~26 to 28 months, nothing much seems to change about the drug development process. Why? Obviously, can't be a simple case of one or two or even three simple factors. Rather, this status quo is the sum of entrenched cultural, technical and commercial imperatives.

Across the board, regardless of company size or therapeutic area, failing late rather than early suggests drug development decision-making appears mired in its version of the Concorde effect, i.e., Sunk costs. Why? As with just about everything in life, outcomes depend on the kinds of behaviors that are rewarded. Here, perverse incentives are one likely explanation. Currently, success for biopharma R&D scientific teams tracks with advancement of their drug candidate, i.e., 'progression-seeking', and not scientific 'truth-seeking' (3). Team members' personal success, promotion, bonuses, organizational influence, these and more depend on their advancing their 'asset' through the drug development pipeline, not on even-handedly examining both the positive and negative scientific data about it. When such a culture prevails, no surprise a drug candidate, aka the 'asset', is more akin to the proverbial hot potato, shunted down the development pipeline to become someone else's responsibility. This is one possibility.

Another major reason could be the pervasive culture of relentless focus on short-term profits. After all, markets react exuberantly every time a drug candidate moves forward in the development pipeline. In turn, company management and shareholders become extremely attuned, even habituated to such reactions. After all these reflect very well on their immediate bottom-lines.

Having the 'right culture' then means something much more consequential than merely rewarding scientific 'truth-seeking'. It means having management with sufficiently strong backbone to eschew short-term profit in favor of long-term success predicated on scientifically extremely thoroughly vetted drug candidates. That entails more investment (money, personnel, resources and time) on the earlier stages of drug development to sort through a bunch of candidates more thoroughly and failing them expeditiously so that a higher proportion of sure bets progress to the next stage.

However, reality shows though that short-term profits remain the major focus for all involved, the scientific teams, the management, the shareholders, the market, usually all the way until the inevitable chickens, i.e., putting off difficult decisions until years down the road, come home to roost in the form of Phase III failures.

Other reasons that feed into lengthy development times and increasing late-stage failures are

a) The notion that treatments for simpler diseases have already been achieved in the past and remaining challenges are much more scientifically difficult. Such challenges include lack of appropriate model systems, of in vitro approaches, of biomarkers, etc., and not knowing or understanding well enough the right patient/tissue/target.

b) Regulatory landscape is increasingly more risk-averse and there's a much higher, perhaps even implausible, bar for safety.

c) Comprehensive health economics weren't part of a given drug candidate's vetting early in the process. Years down the road, when they're finally prioritized, the data suggest insufficient market or vexing reimbursement and/or pricing issues or cost versus benefit analysis renders product inferior to standard of care.

Bibliography

1. Pammolli, Fabio, Laura Magazzini, and Massimo Riccaboni. "The productivity crisis in pharmaceutical R&D." Nature reviews Drug discovery 10.6 (2011): 428-438. http://moglen.law.columbia.edu/t...

2. Mestre-Ferrandiz, Jorge, Jon Sussex, and Adrian Towse. "The R&D cost of a new medicine." London: Office of Health Economics (2012). https://www.google.com/url?sa=t&...

3. Ringel, Michael, et al. "Does size matter in R&D productivity? If not, what does?." Nature Reviews Drug Discovery 12.12 (2013): 901-902. http://media-publications.bcg.co...

4. Morgan, Paul, et al. "Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival." Drug discovery today 17.9 (2012): 419-424.

5. Cook, David, et al. "Lessons learned from the fate of AstraZeneca’s drug pipeline: a five-dimensional framework." Nat Rev Drug Discov 13.6 (2014): 419-431. http://admin.indiaenvironmentpor...

6. Adams, Christopher Paul, and Van Vu Brantner. "Spending on new drug development1." Health economics 19.2 (2010): 130-141. https://www.researchgate.net/pro...

7. Owens, Paul K., et al. "A decade of innovation in pharmaceutical R&D: the Chorus model." Nature Reviews Drug Discovery 14.1 (2015): 17-28.

https://www.quora.com/Is-it-true-that-only-50-of-stage-3-clinical-drug-trials-succeed/answer/Tirumalai-Kamala