At a session at the American Psychoanalytic Association meeting here, Leli said he conducted his first Skype analysis with a Chinese patient in 2004.
"When I did my first Skype analysis, I had many doubts," he said. "Will the analytic process develop? Will there be language differences? Cultural differences?"
He soon began to feel that the Skype analysis was "similar to any type of analysis."
Modern technology can be used to reach and help patients around the world, not just in the doctors office. This example involved a Physicians office in New York and a patient in China for psychoanalysis, both talking on Skype via phone and video.
It's amazing what can be done these days. And then I recall that my own PCP insists on office visits and will barely even use the telephone, except in dire necessity for phoning in a prescription to the local pharmacy. SMS? Never, which is a great shame.
That said, I think it's great that Skype is a great start – imagine what could be done down the line with Cisco's Telepresence?
In December, we started a series on new trends in the pharmaceutical industry and kicked off with a review of the growth in generics.
Today, we're going to take a look at the second big growth trend: emerging markets.
In a sense, one drives the other, because as you can see from the earlier post, the generics share has increased to over 70% and growing, while CAGR in developed countries for Pharma has flattened. In order to drive or even maintain profit margins, manufacturers must therefore seek new opportunities elsewhere.
This leads us to a new trend: the growth of emerging markets, particularly in the BRIC countries (Brazil, Russian, India and China). Part of this is driven by demand as a burgeoning middle class emerges.
Changing diet and lifestyle (usually more Westernised) also brings with it different medical conditions. For example, by 2025, a number of Pharma colleagues told me that they believe 50% of new patients in high growth therapeutic areas such as diabetes and oncology will come from BRIC. That's an astonishing statistic and I'm not even sure it's feasible, but undoubtedly the number is on the rise.
Attractive market dynamics usually mean new market opportunities:
Fast growing economies with strong GDP growth – pharma market growth is strongly correlated with accelerating GDP growth
Demographic changes
Expansion of government healthcare coverage
Increasing purchasing power of growing middle class
The size of a blockbuster, however, is much lower than in developed markets: $25M in India and $100M in China, for example; but affordability is key to successful market access and ultimately, growth.
It isn't all plain sailing though, the markets may be both different and more complex:
Improving but challenging IP environment e.g. Patent enforcement
Investment in local infrastructure required
Differences in local regulatory/healthcare environment
India has the most challenging IP market, but Russia and Brazil are much more respectful and China has improved in leaps and bounds over the last 10 years.
The huge investment required to enter new markets essentially means that big Pharma with its considerable resources and a global infrastructure are more likely to compete than small Pharma and Biotech companies who may still be expanding their operations outside of their home market.
Partnerships and joint ventures with local companies are one way forward for companies looking to expand overseas. Sanofi-aventis just announced one such deal with Minsheng Pharmaceuticals in China, for example, while Pfizer also appear to be eyeing opportunities in China, according to a recent WSJ article. It was interesting that Pfizer saw one key part of success was to develop good relationships with the government and healthcare providers in China:
"For instance, during the SARS crisis of 2003, Pfizer provided China with emergency supplies of anti-fungal drug Vfend, which was used to treat some secondary infections caused by the virus. That drug is now widely used around China despite not having a local patent."
In many ways, big Pharma companies with a strong generics arm may have an advantage, because the initial opportunity will be in marketing generic drugs and vaccines to the new markets.
GSK is focused on developing joint ventures in China to market its vaccines for MMR and flu. Last June, a joint venture with Shenzhen Neptunus Interlong Bio-Technique Co. Ltd (Shenzhen Neptunus) was announced to market flu vaccines. Then in October, a new joint venture was announced with the Jiangsu Walvax Biotech Company (Walvax) to develop and manufacture pediatric vaccines such as MMR. Under the terms of this deal, GSK stated in the press release:
"Specifically, GSK will provide access to its proprietary adjuvant system which helps to improve efficiency and optimise production by increasing the number of vaccine doses that can be produced using a smaller amount of antigen. Shenzhen Neptunus will provide additional local manufacturing capacity and R&D expertise. Both companies will provide further investment in manufacturing."
Who are the big players in the emerging markets, you might well be wondering? Me too, and a nifty chart in one of the sanofi-aventis analyst presentations provides the answer (I'm assuming the data came from IMS):
In many ways, this is the new frontier and the race is on to compete in emerging markets as they start opening up to big Pharma. Interestingly, several of the above companies are strong in generics as well a branded pharmaceuticals.
My pie in the sky prediction is that these emerging markets won't stay cheap for long though, they never do and no one wants to feel they live in a poor and developing nation. The new emerging markets are vibrant and energetic, part of a new world order where the long term shifts and patterns are already changing.
Before closing, I'll leave you with an absolutely fascinating Ted talk from a Professor of Global Health who makes data sing, Dr Hans Rosling. He is from the highly renowned Karolinska Institute in Sweden. He covers this concept with gusto and brings it to life – the emerging markets are stronger than many believe, while the old world order is much more fragile than it appears:
As Sting would say, "There is a deeper world than this, listen to me girl…."
It's been a while since I took a look at what's happening in the prostate cancer arena, but it seems a good time after the recent flurry on lung and colorectal cancers, especially as it's Groundhog Day :-).
There are three particular agents that I'm interested in:
I'm going to spend most of this post talking about the first two, as much has been said on Dendreon already.
Dendreon filed their amended BLA on November, and the FDA have given a PDUFA date of 1 May 2010. The data from 512 patients showed an improvement of 4 months survival for Provenge over placebo, meeting the FDA's threshold.
We have, however, no idea how the vaccine would have done compared to standard chemotherapy such as docetaxel plus prednisone, and therein lies the rub. Normally, in oncology trials we compare the standard of care with and without the new agent or compare the standard therapy to a different regimen. Placebo controlled trials have not done well with ODAC and the FDA, as J&J, Vion and Genzyme all learned with placebo controlled trials in elderly AML patients.
Regular readers of Pharma Strategy Blog will know I'm not a big fan of either placebo trials in cancer or vaccines, so we'll wait and see what the FDA decide. My expectation is that it will receive approval this time round having jumped through the extra hoops.
Cougar Biotech and J&J are developing abiraterone in advanced prostate cancer. A phase III trial in asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer began enrolling this month.
It's estimated to complete in April 2014 and the primary endpoint is overall survival, but initial results should be available in April 2011 for progression free survival at 12 months from what I can see, so perhaps there will be some data around ASCO in 2011. Based on that data I can't see a filing much before the 2nd half of 2011 at the very earliest, possibly not until 2014.
Looking at J&J's analyst presentations, I found the following timeline for their pipeline:
Now, many drugs are lumped together in the 2011 timeframe across 3 columns. It isn't clear whether each column represents 2011, 2012 and 2013 or it's a random list of drugs that will be filed in that period. Either way, it's hard to see abiraterone getting accelerated approval so my assumption for now is abiraterone will be filed in 2013, with approval in 2014.
It's not going to be a fast development: Cougar is very inexperienced and J&J are relatively weak and slow in oncology.
The asymptomatic nature of the patients will also complicate things because it's a high risk study that may not show much in the end. If it works, great! That said, I'm not sure how well the results will fare in what looks like a fluffy trial design comparing abiraterone plus prednisone to placebo plus prednisone. Patients are specifically excluded if they have received prior chemotherapy. Well then, why not compare abiraterone to docetaxel, which is the current standard of care in castration-resistant disease, given that this is a front-line trial?
Recently, at the AACR Molecular Targets meeting in Boston, I had the pleasure of listening to a most excellent talk from Dr Charles Sawyers (MSKCC), one of may favourite researchers. He covered a lot of ground on the lessons learned in targeted agents, principally in CML and prostate cancer.
With regards to prostate cancer, he showed a graphic similar to this one (from Medivation):
Clearly, there are a number of opportunities to explore for the development of new drugs for the disease after hormome therapy ceases to work. This is where traditional drug development for chemotherapies typically starts.
What was interesting about Sawyers talk is his discussion about the androgen receptor (AR) and whether or not it is important in castration resistant disease.
Previously, AR was thought to be irrelevant in this situation because it is not expressed in 2 common prostate cancer cell lines, but Sawyers argued cogently that this shows a failure to appreciate the potency of inhibition because AR is restored through PSA production. Several reasons have been evaluated for this, including AR amplification, mutation and alternative pathways among others. AR is also overexpressed in castration resistant xenograph models, and can confer castration resistance.
What followed was an elegant discourse showing that MDV3100 is distinct from bicalutamide, whereby it has a greater affinity, binds AR selectively, without displaying agonism in AR overexpressing cells and has more potent antagonistic activity.
In the end, Sawyers argued that what was important was not AR overexpression per se, but AR amplification because prostate cancer cells with natural AR amplification are more sensitive to AR knockdown than AR single copy prostate cancer. Minor AR knockdown is sufficient to inhibit growth of AR amplified disease. All of this leads us logically to an important question:
Are AR amplified prostate cancers a different (and important) patient subtype?
Clinical trials with MDV3100 have demonstrated that at least half of prostate cancer patients remain AR dependent, suggesting that this is indeed the case. Clearly, if you can keep patients hormone sensitive or at least responding to therapies using different approaches, then the opportunity to delay time to metastasis and late stage disease may well exist with these novel approaches.
A lot of Pharma people often ask about the ROI or Return on Investment of new media, including social media. The reality, though, is that it's a lot more complicated than that.
Why?
Because the value of any marketing or sales channel is more than just push marketing and measuring the impact on various metrics. It's about building strong relationships in time, rather than investment in money. My friend Rory Murray calls this "return on relationships".
Think about the experienced sales reps who have been seeing the same doctors for years, have built a network of relationships and generally hate marketing stuff. They don't sell successfully from detail aids, they do well because the doctors have formed a relationship and like and trust them.
The same thing happens in marketing and managed care.
Remember those KOL's? The brand that builds solid and strong relationships with the academic experts has more influence than the one that doesn't. Doctors often buy on emotion, not logic. Those who have good channel relationships in appropriate managed care areas do considerably better than those who don't, as Lilly found out to it's cost with Effient recently.
If you put all of those aspects together, you can see that a launch success or failure is almost predicted from the start.
So how can social media help?
Well, think of it as a way of strengthening your online reputation; if you push stuff out there but don't engage, what does that tell customers and consumers about you? Ultimately, that approach will weaken your image. However, if you appear engaged, authentic, helpful and sincere then inevitably, people will have a more favourable impression. This is why I like the way some Pharma Twitter accounts such as Roche and Boehringer interact with people. They answer questions, provide information and generally do a nice job of being cheerful and responsive without being pushy.
With others, though, it's like getting blood out of a stone. They don't seem to listen or interact and constantly push out stuff in a semi advertorial fashion; it's all about them, not the consumers or listeners. Of course, that approach has influenced my opinion of the company and its products more negatively.
Rory recently posted a short presentation, which I highly recommend. Take a quick look at what he has to say:
One of the books I am currently reading, when I am not frantically busy consulting on social media, new product development, competitive intelligence, strategic landscape opportunity assessments, disease overviews or even KOL market research studies, is “Negotiation Genius" by Deepak Malhotra and Max Bazerman of Harvard Business School.
They draw attention to the concept of “parasitic value creation” in the pharmaceutical industry and how this occurs when a pharmaceutical company pays a generics company to stay out of the market. Despite the fact that the Federal Trade Commission (FTC) considers such deals illegal, there are numerous examples of this occurring.
How does it work?
Malhotra and Bazerman describe the scenario of a Pharma company with a drug earning $400M profit per year, where the introduction of a generic competitor will lower profit to $180M for the pharma company and generate $100M of profit for the generics company i.e. a combined profitability of $280M. If the Pharma company pays the Generic company $125M to stay out of the market, both parties appear to win: the generics company receives more profit than it would have with competition and the Pharma company obtains profits of $400M less $125M i.e. $275M which is more than the $180M it would have received in competition with the generic.
It appears to be the perfect business solution on paper i.e. by working together the companies have maintained a $400M market rather than reduced it to a $280M one. Anyone familiar with the prisoner’s dilemma in negotiating strategy will know that co-operation has the maximum payoff in game theory.
However, Malhotra and Bazerman ask the question where does the $120M in value that was “created” by co-operation come from ? The answer is that it is generated from the consumers who must now continue to pay more for the drug than they would if a generic was available. They argue that there has been no value creation only a transfer of value from consumers to producers, therefore it is “parasitic value creation.”
The above might just be interesting negotiation theory were it not for the fact there are numerous apparent deals between generics companies and pharmaceutical companies where payments are made to delay the introduction of generics. The FTC considers “pay for delay” agreements to be an unreasonable restraint of trade that attempts to monopolize the market, and has brought antitrust law suits against companies, with mixed success.
The idea of formally banning “pay to delay” agreements has been discussed as part of the current health care reform. The FTC estimates that stopping this would save consumers $3.5B per year.
Of the $35 billion in savings over ten years, $12 billion would be savings to the Federal government, not an insignificant amount.
It is hard to consider pharmaceutical companies as being “ethical” when parasitic value creation through “pay to delay” occurs, yet like baseball players with steroids, there is always going to be pressure to “cheat” if others are doing it and apparently getting away with it. It will be interesting to watch the ongoing health care reform debate to see if "pay to delay" is addressed as part of it.
Do you believe these deals are fair game and ethical, or not?
Over the last few weeks I've received a bunch of emails from frustrated Pharmers in sales, marketing, PR and even R&D, all wanting to engage and interact with patients while providing better and more accurate information for the general public on a variety of topics.
In each case, these were intelligent people who had got the hang of social media themselves from personal experience and saw the unlimited possibilities it offers.
What was also common is that the organisations involved were all leery of doing anything non-traditional or out of their comfort zone simply because it might not be impossible that some risk might happen, the FDA doesn't have any guidelines and they don't want that responsibility on their shoulders. Who knows what may happen yada yada…?
Granted we live in a highly regulated environment in Pharmaland, but we accept risk in clinical development, why not marketing?
Social media is disruption technology, it makes people uncomfortable. Just as extreme sports don't appeal to everyone, social media is viewed by many as 'extreme marketing'. If your organisation or team is not prepared to deal with a certain amount of chaos, it's probably not ready to handle it.
One trick I've learned for getting things done: don't call it social media and don't focus on the tools – think about the objectives and outcomes you want to achieve; the tools are just a means to an end, not the end in themselves.
The other thing that caught my imagination this week was Apple's iPad launch. This looks like a slick and useful tool for mobile on the road presentations and sharing of data, information, videos, all sorts of things. Who wants to lug around a heavy laptop plus an iPod, a kindle, and whatever other paraphernalia is necessary for a road trip?
Now, imagine those same Pharma people with an iPad on the road. It would allow you to catch up on the scourge of emails, write and edit presentations in iWork, share a short video or clinical synopsis with a doctor, discuss scientific data over coffee easily. Share news, medical or article links on Twitter, search for medical information, develop a team Mind Map around a particular idea, check your territory and team sales, use augmented reality to check a hospital to find the doctor, coffee shop, notes on the account, all with a few simple clicks etc etc.
This is the future of technology, right here, right now.
The intersection of technological changes, social media and digital interaction is changing faster than Pharma can even keep up with it, let alone get started. Tools like the iPad and social media will eventually mesh and a new way of communicating will eventually emerge. Who really needs a printed and out of date detail aid when you can discuss a clinical paper right there on the screen?
Nothing will change until the old guard retire or move on.
In their place is an army of young, dynamic and digitally savvy generation bursting with ideas, enthusiasm and a deep seated desire to do things differently and make change happen.
It's a funny old world: who would have thought that the President's State of the Union address and Apple's iPad announcement would have got me thinking about the chaos that social media causes in Pharma?
A Pharma friend who regularly reads this blog attended the ASCO GI meeting last weekend and phoned me to say that cancer is indeed getting much more complex. She was also highly amused at the buzzword bingo post from the AACR Molecular Targets meeting:
"Well, I just thought you might like to know that the latest buzzword bingo is 'cross-talk'"
Funnily enough, I was writing a report on cross-talk at the very moment she called. Cross-talk occurs when two powerful signaling pathways interact, leading to interactive processes between them downstream of the original receptors.
Another Pharma buddy sent me the slides from a presentation on the Merck IGF-1R inhibitor, MK-0646, phase I results of which were reported in pancreatic cancer. One of the focus of the presentation was 'cross-talk' according to the abstract:
"Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/Akt pathways mediate resistance to anti-EGFR agents such as erlotinib. IGF-1R + EGFR antagonists result in synergistic antitumor activity in preclinical pancreatic cancer models."
When you actually look at the pathways involved, you can see that things are indeed very complex and cross-talk is not surprising, as Pollak et al., showed in 2004:
This means that inhibiting the IGF-1R pathway alone with a inhibitor such as Pfizer's figitumumab or Merck's MK-0646 is unlikely to be effective because cross-talk between the receptor and AKT/mTOR or MEK pathways may well have an impact and lead to an escape route for the cancer cells to continue surviving. For this reason, we can see that the recent futility reported in the figitumumab lung cancer trial is not completely surprising. However, combining the drug with an AKT or MEK inhibitor may well yield better results.
In the Merck study, the majority of patients had an objective response or stable disease when the IGF-1R inhibitor was combined with erlotinib, an EGFR inhibitor. Cross-talk between IGF-1R and EGFR has been shown in preclinical models of pancreatic cancer.
These early results are promising for the compound, but much work is still needed to determine suitable predictive biomarkers and ideal combinations/sequencing before moving forward into a phase III trial.
Pollak, M., Schernhammer, E., & Hankinson, S. (2004). Insulin-like growth factors and neoplasia Nature Reviews Cancer, 4 (7), 505-518 DOI: 10.1038/nrc1387
In the last few weeks, the flurry of posts on non-small cell lung cancer (NSCLC) have triggered some interesting responses and questions in my inbox.
Rather than try and answer them all, I came across this excellent presentation from Dr Sai-Hong Ignatius Ou, who is a lung cancer doctor at the University of Irvine in Southern California. He summarises the issues surrounding EGFR inhibitors, which patients are most likely to respond, and why.
It is an important topic to understand for doctors and patients because there are large pockets of Asian non-smokers in California (and elsewhere in the US) and these patients are most likely to have improved outcomes on erlotinib (Tarceva) or gefitinib (Iressa).
Take a look at his synopsis below. If you like it, it can also be downloaded for later viewing:
A team of UK scientists has made the discovery that drugs that target a fault in a protein called BRAF could actually fuel the progression of cancer in some cases.
The findings of the study, which was jointly funded by Cancer Research UK, the Institute of Cancer Research (ICR) and the Wellcome Trust, are published in Cell.
Malignant melanoma is the most deadly form of skin cancer and is difficult to treat successfully once it has spread to other organs.
The BRAF gene is faulty in about half of malignant melanomas and many other cancers, making it a suitable drug target.
Drugs that block BRAF function in cells are already showing positive results in early clinical trials in melanoma patients in the US.
Hot on the post earlier today about anti-angiogenic drugs causing accelerated tumour invasion when used in the short term, this article on BRAF inhibition was also timely and relevant. One BRAF inhibitor in development, sorafenib (Nexavar) also inhibits VEGF.
The consequence of the CRUK research is that patients need to be carefully screened before deciding upon therapy. Those without a faulty RAS gene could be better candidates for BRAF therapy and those with may encourage the cancer to grow. This may provide a good biomarker in diseases such as melanoma.
The findings give new insights into how the drugs work, and ultimately, how the underlying biology affects tumourigenesis and growth.
As we learn more about the biology of cancer, I’m finding that rather becoming simpler, it actually seems much more complex and sophisticated than we may have first realised.
Sometimes, we don’t know what we don’t know.
Take for example, the recent AACR meeting on the molecular origins of lung cancer that I attended and wrote a few summary posts on (with more to come!)
There was a particularly fascinating lecture from Robert Kerbel, who looked at the role of tyrosine kinase inhibitors (TKIs) in metastatic cancer. He noted that there have been many successful trials with TKI’s, with a two month improvement in survival being typical. There have also been failures, such as bevacizumab (Avastin) in 1st line pancreatic cancer, 2nd and 3rd line breast cancer and adjuvant colorectal cancer.
Numerous theories associated with how anti-angiogenic agents work, including the normalisation of blood vessels, allowing more drug to be delivered to the tumour and several other hypotheses have also been floated around.
What struck me though, was that the switch to a different concept, one where there are early indications that anti-angiogenic therapy actually promotes invasion and metastasis, for example in glioblastoma. Dr Kerbel then showed some scans clearly showing disease progression and growth and asked whether bevacizumab actually increases the aggressiveness of a metastatic tumour over time?
ie
The evidence for this concept came from an paper published in Cancer Cell in 2009 by Paez-Ribes et al.,:
“The realization that potent angiogenesis inhibition can alter the
natural history of tumors by increasing invasion and metastasis
warrants clinical investigation, as the prospect has important
implications for the development of enduring antiangiogenic therapies.”
This invasion effect has been shown in bevacizumab and sunitinib (Sutent), both potent inhibitors of VEGF, so clearly the effect is a class one.
Kerbel discussed what else could explain the results other than increased tumour hypoxia?
Another idea looked at dose dependent circulating levels of plasma VEGF, which Ebos et al., proposed and was subsequently noted with sunitinib in phase II human breast cancer trials reported by Harold Burstein.
The issue then becomes one of potential consequences. Thus, plasma VEGF levels may explain drug resistance seen with anti-angiogenic agents, rapid tumour regrowth and rebound revascularisation may occur once therapy is stopped and an increase in malignant aggressiveness may be seen as invasion and metastasis increases.
The other question on my mind is why is there differences observed in adjuvant and metastatic disease as we have discussed previously with the negative bevacizumab results in adjuvant colorectal cancer. It is possible, based on these observations that treatment with anti-angiogenic agents may have the opposite effect to that intended by hastening progression and thus such therapies may be better suited to the metastatic setting.
The big question now is figuring out how to overcome the drug resistance seen with these agents while minimising the vascular stimulation effects seen.
Pàez-Ribes, M., Allen, E., Hudock, J., Takeda, T., Okuyama, H., Viñals, F., Inoue, M., Bergers, G., Hanahan, D., & Casanovas, O. (2009). Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis Cancer Cell, 15 (3), 220-231 DOI: 10.1016/j.ccr.2009.01.027
Ebos, J., Lee, C., Cruz-Munoz, W., Bjarnason, G., Christensen, J., & Kerbel, R. (2009). Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis Cancer Cell, 15 (3), 232-239 DOI: 10.1016/j.ccr.2009.01.021
Loges, S., Mazzone, M., Hohensinner, P., & Carmeliet, P. (2009). Silencing or Fueling Metastasis with VEGF Inhibitors: Antiangiogenesis Revisited Cancer Cell, 15 (3), 167-170 DOI: 10.1016/j.ccr.2009.02.007
Ebos, J., Lee, C., Christensen, J., Mutsaers, A., & Kerbel, R. (2007). Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy Proceedings of the National Academy of Sciences, 104 (43), 17069-17074 DOI: 10.1073/pnas.0708148104
Burstein, H., Elias, A., Rugo, H., Cobleigh, M., Wolff, A., Eisenberg, P., Lehman, M., Adams, B., Bello, C., DePrimo, S., Baum, C., & Miller, K. (2008). Phase II Study of Sunitinib Malate, an Oral Multitargeted Tyrosine Kinase Inhibitor, in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane Journal of Clinical Oncology, 26 (11), 1810-1816 DOI: 10.1200/JCO.2007.14.5375
Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, & Kerbel RS (2009). Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer cell, 15 (3), 232-9 PMID: 19249681
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