Archive for October 2011
There is no denying that many medicines have their beginnings in traditional medicines. Tales of the healing properties of Chinese herbal medicines or plant treatments used by Native American centuries ago abound. Hundreds of years ago, people knew that chewing the root of the bark of a willow tree relieved their pain. In the 1800s, salicylic was identified as the active component in willow bark and, in 1899, scientists at Bayer synthesized a new form of salicylic acid called acetylsalicylic acid, more commonly known today as aspirin. This is not an isolated example.
The modern drug industry may owe its roots to early traditional medicine and certainly the end goal is the same now as it was hundreds of years ago. But the continued grip of herbal medicines on the general population is astounding. Some weeks ago, Natalie Singer in The New York Times (August 28) reported that last year in the US sales of dietary supplements purported to be used for health benefits came to $28.1 billion, a jump from $21.3 billion in 2005. Consumers of these products are driven to them because of the expectation that natural products are inherently safer than medicines derived from drug companies. Furthermore, there is the belief that centuries of use ensure efficacy. However, studies are showing that this is not always true.
Ginkgo biloba is marketed as an herbal medicine that enhances memory, and it may be the most wideIy consumed herbal treatment used to prevent age-related cognitive decline. Its popularity is attested to by its US sales which exceed $250 million annually. In 2008, the Journal of the American Medical Association published the initial results of the Gingko Evaluation of Memory (GEM) trial (JAMA, 300, 2253 – 2262), a randomized, double-blind, placebo controlled clinical trial designed to test Ginkgo biloba for preventing dementia. GEM was conducted in five academic medical centers in the US between 2000 and 2008 with 3069 volunteers aged 75 or older with normal cognition or mild cognitive impairment. Half of this population received a standardized extract of Ginkgo biloba and half received a placebo; they were followed for an average of 6.1 years. At the end of this time, there was no statistical significance in the occurrence of either dementia or Alzheimer’s disease between the two groups. In other words, Ginkgo biloba had no beneficial effect.
Saw palmetto is extracted from the fruit of Serenoa repens. Native Americans use the saw palmetto berries to treat urinary problems and it has grown popular among older men as a treatment for benign prostatic hyperplasia (BPH). In 2006, the results of the Saw Palmetto Treatment for Enlarged Prostates (STEP) trial were published (New England Journal of Medicine, 354: 557 – 566). This was another multicenter double-blind, randomized, placebo controlled trial comparing 160 mg twice a day of saw palmetto vs. a placebo. Despite looking at a variety of parameters (prostate size, residual volume after voiding, PSA score or quality of life), after one year, there was no difference between the results of saw palmetto and placebo. If this wasn’t sufficient, the results of yet another trial, this one published recently in JAMA (306: 1344 – 1350, September 28, 2011), showed that doubling and then tripling the dose used in the STEP trial for two years also had no effect. Saw palmetto is no more effective than placebo in treating BPH.
One may ask: what’s the harm? These herbal extracts aren’t toxic, and so people should be free to take whatever they’d like. Maybe taking these herbal medicines gives them peace of mind. However, because herbal drugs aren’t nearly as well studied as prescription drugs, there could be issues with them that are unrecognized. For example, does taking either Ginkgo biloba or saw palmetto interfere with the disposition of other medications that one is taking? This idea isn’t farfetched. It is known, for example, that St. John’s wort, a controversial herbal medicine taken by people to treat their depression, limits the effectiveness of a variety of medications, including antiviral agents, birth control pills and some anticancer medications.
If a person wants to take herbal medications, that’s his or her personal choice. But patients should be aware that these medications haven’t been subjected to the rigorous FDA scrutiny that all prescription medicines must receive. Buyer beware.
When the FDA is deciding on the approval or rejection of a new drug or medical device, they often call upon medical experts from around the country. This practice is an excellent way for the agency to tap into the vast amounts of knowledge from leading experts. Theoretically, it’s a great system that ensures patients and physicians get safe and effective medicines.
But, in recent years the FDA has had difficulty in recruiting these advisors. In 2008, the FDA enacted a policy preventing scientists with financial ties to pharmaceutical, biotech and medical device companies from serving on FDA Advisory Committees. The rationale for this policy was pretty simple: any scientist or physician who had advised a biopharmaceutical company might feel obligated to support that company’s position when reviewing one of their drugs or medical devices. The FDA wanted advisors with uncompromised views.
These conflict-of-interest rules developed from events that occurred in the previous decade. One notable example was the issuance of new guidelines for lowering LDL cholesterol by the National Cholesterol Education Program (NCEP), a division of the government’s National Heart, Lung and Blood Institute. The NCEP recommended that all people should have an LDL level no higher than 100 mg/dL and that those patients at high risk for a heart attack and/or stroke should reduce their LDL levels to 70. “Heart officials urge sharply lower cholesterol levels” heralded The New York Times (July 12, 2004). Forbes focused on another aspect of the new guidelines: “Cholesterol Guidelines a gift for Merck, Pfizer” (July 12, 2004) – a clear reference to the fact that the two biggest selling LDL lowering drugs, Zocor and Lipitor, were sold by these companies.
However, concerns about these guidelines arose when people realized that the NCEP panel that made these recommendations was made up largely of physicians who had been paid as consultants or who had been involved in the clinical trials of the very same drugs that would now be used more extensively. Consumer groups and others began to challenge whether these panelists had the ability to act in the public’s best interests. While this example focuses on the NCEP Guidelines, similar examples were cropping up in other disease areas as well. As a result, the FDA began to use advisors with minimal industry ties. This measure is now proving to be an obstacle in the FDA’s recruiting process.
Pharmaceutical companies draw heavily upon experts for a variety of reasons. These experts are in demand to lead or to play a part in running clinical trials for a company’s major new drugs. These same experts are sought to comment on clinical design strategies, or to provide advice on new breakthroughs in understanding diseases. These scientist/physicians are even sought to participate in “mock advisory committee meetings” that a company will have to prepare for a real FDA Advisory Committee hearing. When companies do this, they will always try to get the leaders in the field. These leaders can and do command high fees for their services, and these fees preclude them from advising the FDA.
Part of the problem also comes from the natural progression of drug discovery and development. The clinical studies are obviously done way in advance of the filing of a New Drug Application (NDA). Thus, many experts are “conflicted” long before there is even the possibility of scheduling an FDA Advisory meeting to review an NDA. When you consider that there are many companies working in every therapeutic area and that the pool of experts is finite, it’s no wonder that the number of people left for the FDA to choose from is pretty small.
A few months ago, FDA Commissioner Margaret Hamberg told a congressional committee that the FDA will seek to loosen the conflict-of-interest rules in 2012. She testified that: “We have to be sure that FDA has subject-matter experts that we need for our important decision making” (Bloomberg, 7/25/2011). Just last week, three Senators (Klobuchar, MN.; Burr, NC; Bennet, CO) proposed legislation that would loosen the conflict-of-interest rules for FDA advisors (Reuters, 10/13/11). A similar bill is anticipated from the House of Representatives.
These changes will help the FDA in recruiting advisors. But the changes will not be embraced. Be prepared for a host of consumer groups to decry these efforts with claims that the FDA is again cozying up to Big Pharma and seeking advice from biased scientists and physicians. Once again, the FDA is stuck in the middle. But the system is workable. To be effective, all FDA advisors will need to have complete disclosure with whatever ties they have to commercial entities. In addition, complete financial disclosures of the payments they have received will need to be available to afford complete transparency. In fairness, many physicians already do this. Finally, at some point we need to trust these physicians and scientists to do the right thing, that they will advise the FDA based on scientific data and not their corporate affiliation. I think the medical community is more than able to handle this responsibility ethically.
Last February’s comments by Kenneth Frazier, Merck’s CEO, should have served as an inspiration for those focused on the promise of new medicines and perhaps acted as a beacon for other leaders in the pharmaceutical field. As reported by Jonathan Rockoff in The Wall Street Journal (February 4, 2011), Frazier said that Merck will not focus on cuts, but rather focus on investing in drug development to drive growth. He said that he wanted to reinvest some of the savings realized from the acquisition of Schering-Plough into advancing Merck’s last stage pipeline. Frazier continued on this theme at his company’s annual shareholder meeting in May, where he shared his vision of success by using Apple, IBM and Starbucks as examples. These companies succeeded through innovation and he said that innovation and research were key to his vision for Merck (Susan Todd, The Star Ledger, May 24).
Wall Street analysts, however, weren’t happy. Les Funtleyder, a manager of the Miller Taback Health Care Transformation Fund, provided a typical response: “Merck could end up wasting billions of dollars probing compounds that don’t pan out.” Analysts contrasted Merck’s approach to that of Pfizer, which was cutting its R&D budget drastically. The result: Pfizer’s stock price advanced while Merck’s took a hit. Frazier has relented a bit. In late July he announced that Merck would lay off 17,000 colleagues. “Spanked by Wall Street, Merck CEO Orders U-Turn” reported Jim Edwards on the BNET Blog (July 29th). Frazier apparently plans to cut other parts of the company deeply; growth of the R&D division resulting from reinvested cost savings appears to be tabled.
The Merck situation is not unique. John Lechleiter, Lilly’s CEO, has also committed to strong R&D investments for his company. He told Reuters (June 30) that: “It would be a mistake for us to disinvest in any significant way in R&D.” He also realizes that such a strategy is frowned upon by Wall Street: “I never thought that I would live to see this, but investors are actually thinking to cut R&D – that’s the hot topic of the day. This is kind of nuts, but this is what is being talked about.” Analysts have been negative on Lechleiter’s stance.
Amgen is another company in the crosshairs of Wall Street. Just last week it announced that it would be restructuring R&D, with an aim on improving focus and reallocating resources to key pipeline assets and activities. Amgen is a success story. Once a start-up company, it is now the world’s largest biotech. It has been used as an example of how to do this. And what has been the response of the market analysts to this restructuring? Michael Yee of RBC Capital Markets told Reuters (October 12) that “The $3 billion R&D line item annually is high and investors see room to start to trim this.”
Now, I am all for monitoring R&D budgets to maximize the returns from these investments. And I am all for accountability – asking the R&D organization to deliver new candidates to the pipeline, having formal goals with rigorous deadlines, and for running clinical trials as expeditiously as possible while keeping a close eye on costs. But for Wall Street to reward a company for lowering R&D spending and attack those that want to commit to R&D is absurd. Like it or not, R&D IS the engine that powers a pharmaceutical company. It is also a high-risk endeavor. Furthermore, given all of the hurdles that now exist especially with regard to ensuring safety and having sufficient novelty to justify pricing, R&D is more expensive than ever. But, if you want to succeed, you have to invest – substantially. There are no short cuts.
Analysts have said that, in the past decade, the return on investment (ROI) in pharma R&D has been poor. I don’t disagree with that. A strong driver for this has been the spiraling costs in carrying out comprehensive phase 3 trials – a major change from a decade ago. However, this has largely been built into the R&D process and there should now be improvements in the number of new drugs approved annually. Evidence of this comes from an unbiased observer, FDA Director Dr. Janet Woodcock, who recently told Congress that the FDA is approving more new medicines than in the recent past and that these new drugs “work differently, or better, than existing drugs or tackle ailments lacking good treatments.” My guess is that the drugs that will be launched over the next five years will greatly improve the return on investment statistics now used to skewer recent R&D investments, thereby resulting in improved ROIs.
But the decision on how much to invest in R&D, the lifeblood of a company, is the responsibility of the CEO and his Board of Directors. For this to be influenced by Wall Street Analysts is, to quote Lechleiter, “Nuts.”
As many people try to provide explanations of the relative decline of the productivity of R&D groups in Big Pharma, inevitably the terms “large,” “bureaucratic” and “cumbersome” are used. As a result, these same people point to the advantage that biotech presumably has because its small size enhances agility, quick decision-making and collaboration. These perceptions have turned into truisms as Big Pharma has moved to emulate small companies by creating small R&D units.
Biotech R&D is an important component of the discovery and development of new medicines. However, the perception that this sector is more successful than Big Pharma is incorrect. As shown by Gary Pisano in “Science Business – the Promise, the Reality and the Future of Biotech” (Harvard Business School Press, 2006), there really isn’t much of a difference in the success rates of either group. Furthermore, in his blog post “Our Shrinking Biopharma Ecosystem” ( LifeSciVC, 9/9/11), Bruce Booth voices his concerns that the number of Biotech companies is declining as investment funds for these ventures are eroding. There is a lot of pressure these days on existing Biotechs to deliver, which is a direct result of the venture capitalists (VCs) who have funded these start-ups wanting a more immediate return of their investments.
Thus, it is not unusual when talking to the CEO of a biotech company to ask: “How long is your runway?” – meaning, how much time do you have until your funding runs out? This sounds awful, but it may be an unintended advantage that a start-up company has over Big Pharma.
Generally, a Biotech begins by raising funds from a variety of venture capital companies. These funds are meant to be able to get the start-up to a key decision point, a proof-of-concept (POC) study that supports the original scientific idea that the company was founded upon. At that point, if the POC study is successful, the VCs can decide whether to invest more funds or to sell the company to Big Pharma to complete the emerging drug’s development. But the Biotech’s funding is fixed, and its Board of Directors, themselves members of those VC companies that are invested in the enterprise, closely monitor all the company does, especially its “burn rate” , i.e. cash spend.
This type of situation has its appeal. By necessity the scientists have to be extremely diligent with little room for error. Every experiment has to be weighed for its cost and potential benefit. But it also can be debilitating. I once asked Roger Newton, then the CEO of Esperion, how he chose the doses for a crucial POC study his company carried out. Roger was developing a potential new drug that had the promise of reversing atherosclerosis. Roger revealed that the study design was based on the limited amount of drug material that they had. He wanted to run two doses in his Phase 2 trial, one higher than the other, and so he simply divided the amount of drug that he had with one-third being the low dose and two-thirds being the high dose. While clearly not an ideal situation, his POC study worked well enough that Pfizer bought his company. You can argue that Roger was lucky. If he had less material, his study probably would not have worked.
The Esperion example would have been handled differently in Big Pharma. The research funds would have been available to make enough drug to run not two doses but more likely three, and there would have been a strong rationale to the dose selection. While more expensive and time consuming, such a study would have been assured of providing a more definitive answer as to whether the drug worked or not. Furthermore, had the study failed and it was thought that the knowledge generated in the first study warranted a second trial, this would have been done if the program was deemed important enough. That was a luxury that Roger didn’t have. For him it was “one and done.”
In general, this sense of urgency, or more appropriately, this sense of survival, doesn’t exist in Big Pharma R&D. That is not to say that Big Pharma scientists don’t work hard, or waste resources – far from it. These are extremely committed individuals. Furthermore, I am not one who believes that you become stronger by living under duress. I think that the creative process flows better when you can focus on your work and not worry about getting your next job when your Biotech company’s funds run out in nine months.
However, I think there are some learnings from Biotech that can be applied to Big Pharma. Setting time limits for programs can instill a sense of urgency. If you are committed to a research program, and you know it will end in less than a year, you will certainly focus on the key experiments. Admittedly, you are not threatened with losing your job if all doesn’t go well, but after having committed yourself to a program for one or two years, you want to be sure you’ve done all you can to make it succeed before you move on to a new project. Having set time points for project progression also is important. Recently, speaking to a friend who is the CEO of a Biotech, it was mentioned that the Phase 1 start of a key compound was delayed by two months and that the Board was very unhappy. In Big Pharma, such a delay is not always noted as you are managing a portfolio of over 100 such compounds. Program progress should be routinely reviewed. Delays – as well as the occasional accelerated progress – should be duly evaluated. Finally, realistic budgets should be created and closely monitored.
The term “research management’ is not an oxymoron. R&D is not some black box from which you hope something worthwhile will emerge. While it is a creative process, it can be managed, and Biotech lessons can help.
Last week’s headlines were pretty impressive:
“Smokers quit with cheap Bulgarian remedy. For as little as $6, there may be a smoking-cessation remedy that actually works.” Marthe Fourcade, Bloomberg, 9/29/11
“Soviet-era pill from Bulgaria helps smokers quit.” Maria Cheng, Associated Press, 9/29/11
“Smokers get chance to beat the habit with 12 pence tablets.” Denis Campbell, The Guardian, 9/28/11
This publicity was generated by a paper in The New England Journal of Medicine entitled “Placebo-Controlled Trial of Cytisine for Smoking Cessation” (N. Engl. J. Med. 2011; 365: 1193-1200). In this double-blind study, 740 smokers were equally divided into two groups: one taking a cytisine preparation sold in Bulgaria as Tabex, the other given placebo. After 4 weeks of dosing, treatment was stopped and the patients were monitored for a year, after which time 8.4% (31 participants) on cytisine and 2.4% (9 participants) on placebo had quit smoking. How does this compare with other smoking cessation regimens? A similar type of smoking cessation study published in the Journal of the American Medical Association (JAMA, 2006; 296: 56 – 63) showed that Chantix (varenicline) provided 23% continuous abstinence, buproprion 14.6% and placebo 10.3%.
The cytisine study is noteworthy in that, while its anti-smoking effects have been known for over 40 years, this is the first reported clinical trial done in a double-blind placebo controlled manner as required by regulatory agencies like the FDA. But the real driver and interest in this work is the fact that the Tabex brand of cytisine is cheap and available on-line. The leader of the NEJM study, Professor Robert West, predicted that “the publicity surrounding his findings would trigger a surge in people turning to websites to obtain it.” Costs of smoking cessation products vary from country to country, but generally the cost of a course of cytisine therapy is about 10 – 20% that of Chantix. That difference could mean big savings to agencies like Britain’s National Health Service and Medicare in the US.
But let’s not rush to get this drug just yet.
There are still few issues that need to be addressed. First of all, how effective is cytisine compared to the currently marketed agents? Unfortunately, the NEJM study does not include a “positive comparator,” either Chantix or buproprion, so that one can get a sense of how the efficacy of a current treatment compares directly with cytisine in the same study. Looking at the data, it doesn’t seem that cytisine is as effective as the other compounds. If cytisine is only half as effective in causing people to quit smoking, that will cause payers, physicians and patients to think twice about going to cytisine.
However, there is a much bigger issue facing cytisine use – safety. While Tabex had been available in all former socialist countries since the early 1960s, it was withdrawn by many of these countries when they joined the European Union. Safety concerns could have been the reason. The Tabex preparation originates from the plant “Cytisus laborinum L.” Interestingly, there are reports of people getting poisoned with the seeds of this plant. J.F. Etter, in the review article “Cytisine for smoking cessation” (Arch. Intern. Med. 2006; 166, 1553 – 1559), states that “Poisoning in children who eat laborinum seeds is frequent” and that “in an average summer over 3,000 children are admitted to hospitals in England and Wales because of laborinum poisoning.” The symptoms, which include nausea, abdominal pain, respiratory stimulation, and muscle weakness, are consistent with poisoning symptoms with nicotine, which is related chemically as cytisine. Clearly, eating these seeds results in a large overdose of cytisine and the Tabex dose levels of cytisine are much lower. But this points out the need for extensive safety studies for cytisine. The side-effects of Chantix and bupropion are well-known. But these adverse effects were found as a result of the extensive data safety monitoring that has been accumulated by the manufactures over the years these drugs have been on the market. To my knowledge, such an adverse event monitoring system has not been in place for Tabex.
Peter Hajek, director of the Tobacco Dependence Unit at Queen Marry University Hospital in London, said the following to the Associated Press: “It is possible that extensive bureaucracy and over cautious regulations will prevent its (cytisine’s) use in the U.S. and Europe.” One would think that a person in his position would want to be assured of the safety of a drug before it was extensively prescribed.
There is no doubt that cytisine, in the form of Tabex, is a cheap way to help one stop smoking. But is it more effective and safer than existing medicines? That can’t be answered with the current data and more studies are needed. Furthermore, by the time these types of clinical trials are carried out, the generic form of Chantix, varenicline, will be available (2018), making the cost arguments moot.