By Lisa Henderson, Editor-in-Chief, Applied Clinical Trials.

In December 2011, the President’s Bioethics Commission released its “Moral Science: Protecting Participants in Human Subjects Research“. The report was ordered by President Obama following an October 2010 revelation that the US Public Health Service supported unethical research in Guatemala from 1946 to 1948 that involved intentionally exposing thousands of Guatemalans to sexually transmitted diseases without their consent.

The Bioethics Commission was then tasked to oversee a thorough fact-finding investigation into the specifics of the studies, as well as assure that current rules for research participants protect people from harm or unethical treatment, domestically as well as internationally.

The final report, available at this link and specifies 14 changes to current practice to better protect research subjects, as well as how the government should improve the tracking its over 18 federal agencies that follow the common rule for research programs with taxpayer dollars.

So again, this is specifically for government-funded studies and you can read all the different arms that receive funds, including the CIA, but of course the largest is the NIH. One of the Commission recommendations is:

“…. each federal department or agency supporting research with human subjects maintain a core set of data for their research programs that includes the title and lead investigator of each project, the location of each study, and the amount appropriated for the research. Each office should aid the public in learning more about the government’s research efforts by developing or improving publicly available electronic systems or releasing information through a government-wide system. To support these efforts, the Commission suggested that the Office for Human Research Protections or another office should administer a central web-based portal that links to each individual department or agency system. In addition, the government should consider developing a unified federal research database, which may ultimately be more cost-effective and efficient.”

Is it me or does it not sound like the “central web-based portal” or the “unified federal research database” be clinicaltrials.gov?

While the Commission could not easily identify how many research participants were enrolled in federal research (and not all of this is drug/interventional studies), they rounded it off to about 50,000 people.

So in doing the math, I’m assuming there are well over 18 biopharmaceutical companies that are conducting privately-funded research and are required by law to input this information into the clinicaltrials.gov online web database. And when these many biopharma companies fail to comply with this rule, as many critics will publicly announce as often as possible, the biopharma industry suffers another public perception setback and a trust issue.

In the meantime, wouldn’t managing 18 separate departments be akin to managing 18 privately-funded entitites? Each with their own culture, set of employees and roles, data and technology practices, and require that it happen within a certain timeframe?

I think so. I don’t think there need be separate rules for protecting human subjects in research. Nor should there be separate ways to educate the public on how to better serve their health or medical understanding. It’s everybody’s problem, private and public.

Julian Mosquera

The pharmaceuticals industry is undergoing major disruption and every comparative benchmark indicates that the sector needs to make a step change in asset performance, with working capital targeted for direct improvement. All players are planning major reconfigurations of their supply and distribution operations, from end to end, in a bid to improve cost and service efficiency. This challenge is all the more prescient with a large number of blockbusters coming off patent over the next five years, opening the door to generic producers, who are actively “forging strategic alliances” to secure the rights to produce cheaper copies, according to researchers at Frost & Sullivan. While expenditure on new medicine has risen dramatically over the past decade, regulatory approval for new drugs has declined. Where big pharma could turn to blockbusters in the past, they are now looking to smarter portfolio management for competitive advantage.

Historical margins meant pharma paid little attention to their supply chains. However, over the last decade such complacency has become unacceptable to boards. Directors in the current environment are looking to their COOs and supply chain directors to build resilience into supply chain networks, to protect against market volatility and to drive real cost reduction.

The industry’s manufacturing footprint is increasingly challenged by significant overcapacity. Efficiency, agility and flexibility are priorities, with slow moving/low volume production calling for a different supply approach. Now, more than ever, companies should look to increase product speed through the supply chain, challenging inventory touch and holding points in every market in which they operate.
Managing the chill chain is producing real challenges for the sector. As part of a much wider traceability issue, the sector has been slow to adopt the necessary technology and levels of control that may be expected of such a high-value, sensitive product line. Reliance on third parties to introduce such capabilities has had limited success. It is time for the sector to upgrade its capabilities as the new pharma supply chains emerge over the next decade, where chill control and traceability challenges will be far more critical.

There is an opportunity for companies to better leverage scale through structural change, working towards best practices, and most notably by improving and integrating sales and operations planning — something that is commonplace in other industries such as FMCG. Competition is becoming fierce, putting emphasis onto accurate forecasting and supply chain visibility.

Supply chain cost management is now a priority. Having leveraged scale and rationalised productive capacity businesses are looking for further cost-savings. The global nature of distribution has given rise to over-complex and under-managed supply chains, which are now recognised as a source of major cost reductions. Without a clear framework for delivering these savings, businesses are at risk of compromising service and the integrity of supply.

In this context, it is alarming how few pharma businesses know with any accuracy their ‘Cost to Serve’. Which products, distribution channels, customers or regions need more attention, and which need less? How should stock holding policies be tuned to these different groups? Where can lead times or touch points be reduced? Cost to Serve allows companies to calculate the true cost of servicing any combination of customer, product or market and takes a truly end-to-end approach (materials sourcing, manufacturing, logistics, distribution and consumption). By establishing clear policies for customer-product groupings, alongside disciplined, systematic control, it is possible to realise dramatic and permanent cost reductions.

Julian Mosquera is a Director at LCP Consulting, a specialist in customer-driven supply chain management.

FDA approved 35 innovative drugs in fiscal 2011, including treatments for hepatitis C, prostate cancer, Hodgkin’s lymphoma, and lupus. This number of approvals is among the highest in the past 10 years, and it reflects the agency’s efforts to hasten patients’ access to new drugs. In the past two years, the agency’s lower levels of approvals—21 drugs in 2010 and 25 in 2009—caused concern throughout the industry and in Congress. We may feel grateful to FDA, but we also should ask how the agency achieved this high number of approvals.

One technique was accelerated approval for drugs to treat serious diseases. This authority allows the agency to approve a drug based on clinical data showing that it is reasonably likely to have a clinical benefit, even if data do not demonstrate that the drug has this benefit. Almost half of the newly approved drugs received Priority Review because they had the potential to offer major advances in treatment, or because no adequate therapy existed. FDA sets a six-month target date to review such drugs.

Although these changes in procedure are well-intentioned, we may legitimately ask how they will affect patients’ safety. After all, GSK’s diabetes drug Avandia received fast-track approval, but an article published in The New England Journal of Medicine later linked the drug to an increased risk of heart attacks. The Wall Street Journal notes that a Senate Finance Committee report last year accused the company of hiding data showing Avandia’s cardiovascular risks, and GSK has just agreed to pay the US government $3 billion to settle this and other claims.

Creating a short timeline for drug approval could hurt the agency’s reviews of clinical data. FDA approved Pfizer’s smoking-cessation drug Chantix after an accelerated priority-review process. The agency concluded that the drug did not increase the risk of psychiatric problems such as depression. But researchers from Wake Forest Baptist Medical Center found that Chantix was eight times more likely to result in suicidal behavior or depression than nicotine-replacement products. One reason for the discrepancy could be that, unlike FDA, the researchers performed disproportionality analysis on the data—a technique that is increasingly being used to find links in side-effect data that normally escape detection in clinical trials.

FDA’s staff includes well-vetted and experienced scientists, but they need sufficient time to work thoughtfully and thoroughly. Even though the agency’s initiative has increased the number of new-drug approvals, it may also be increasing the risk that a company can hide negative data from regulators, or that the agency’s own analyses will not be as complete as they could be. In light of the problems with Avandia and the conflicting studies about Chantix, I think FDA should review its efforts to promote innovation to be sure that the agency maintains high standards for drug safety.

Erik Greb

Getting FDA approval on a brand name for vandetanib, AstraZeneca’s very first orphan drug, isn’t the only challenge the company has faced during launch. The size of the patient population eligible for Caprelsa is decidedly small, but ultimately fuzzy. “We don’t really know how many patients there are at any given time,” says Eric Vogel, executive director of oncology, at AstraZeneca. “In some reports its 1,000 [in the US], and the FDA thinks it may be 2,000 to 2,500.” Compounding the difficulties presented by a tiny patient population, relatively speaking, is the fact that not all medullary thyroid cancer patients would benefit from Caprelsa; the drug is indicated only for patients whose cancer “has progressed to the point where surgery is no longer an option.”

Vogel says the company is “learning as we go” during the launch. “We believe that roughly half of the patient population will end up in the major treatment centers around the country, but that the other half may or may not continue to be followed by the community endocrinologist or medical oncologist,” says Vogel. Traditional market research hasn’t uncovered a network of physicians treating medullary thyroid cancer, since Caprelsa represents the first pharmaceutical treatment option for those patients, says Vogel. “There are some things that we can do to find physicians that look like they might be treating [medullary thyroid cancer], but it’s an inexact science at this point.”

AstraZeneca signed an exclusive distribution deal with Biologics, an oncology management company and specialty pharmacy, last April. Biologics also distributes AstraZeneca’s Arimidex, as well as Novartis’ Afinitor, Gleevec and Tasigna, Bayer/Onyx’s Nexavar, Celgene’s Revlimid, BMS/Otsuka’s Sprycel, Pfizer’s Stutent, Merck’s Zolinza, Roche/Genentech’s Xeloda and others, according to an “in stock” list on the company’s website. The decision to partner with Biologics for distribution had to do with the size of the patient population, and the amount of support that patients using Caprelsa would need, says Vogel. “We’re pleased with the relationship. [Biologics] spends 45 minutes, on average, with each patient, according to the reports we get from them,” Vogel says. Biologics, for its part, provided a team of 10 nurse liaisons tasked with educating physicians about the drug, and easing the administrative burden on the physician’s practice, Dan Duffy, executive VP and general manager, oncology pharmacy services group, told PharmExec.

In addition to Biologics’ nurse liaisons, AstraZeneca has deployed “regional scientific managers” – physician and/or nurse-facing individuals, to “communicate to our HCP audience about risks associated with Caprelsa, the REMS programs and all of the precautions, as well as any questions they might have around the efficacy or safety of the product,” says Vogel. The REMS program has helped AstraZeneca identify customers, since physicians have to become certified through REMS before prescribing the drug. “Down the road, we may broaden our reach out to community oncologists, those who we’re already calling on with our sales forces for Faslodex,” says Vogel.

The company hopes new indications will be forthcoming, and is currently looking to Europe for the next Caprelsa launch. Laura Woodin, senior manager, corporate affairs, said in an email that Caprelsa is being evaluated in “more than 40 early-stage studies” and various tumor types, including pancreatic, glioblastoma (brain), biliary tract (liver duct), as well as two other forms of thyroid cancer, papillary and follicular. “We’re trying to take our learnings from the US and apply those to other markets,” says Vogel. In terms of a possible launch in the EU, Vogel says the patient population size across Europe is roughly the same as the US patient size, but right now, “it’s not efficient to commercialize [Caprelsa] country by country.” “We will commercialize it country by country as we get new indications, but we have to look at it more broadly by much larger markets” for now, says Vogel.

Caprelsa is currently under review with the European Medicines Agency (EMA) and Health Canada, according to Woodin.

A routine monthly inspection carried out by the Food and Drugs Administration (FDA) authorities in the state of Maharashtra, India, last month noted an increase in the number of sub-standard drug samples raising apprehensions about the availability of safe and genuine drugs in the state.
Officials pointed out that 26 drug samples were found to be spurious, compared with the 16 samples that were not-of-standard quality detected in May and 20 in April. Reportedly, some Ampicillin and Amoxycillin formulations did not have any active ingredients, while others had 6% to 30%. Thiamine tablets with Vitamin B1 and diclofenac sodium, Paracetamol and Magnesium Trisilicate tablets were also found to be sub-standard, officials said.

While some of the offenders are well-known drug manufacturers (like Alkem Laboratories for omeprazole capsules and Venus Biosciences for Odicin-200), many are small drugmakers, such as Affy Pharma for levocetirizine tablets, Medipol Pharmaceuticals India for clauvmentin dry syrup, Endolabs for paracetamol tablets, Softsule for DIAX OD, Therachem Laboratories for Metflox, Medopharm for Miliclav dry syrup/ amoxycilin and potassium CLA.S, Biocin Healthcare for Thyomin tablets and Nuclotec Remedies for Digizyme syrup.

Sub-standard drugs from India has been a major issue for some time now, though the FDA says its crackdown has ensured a significant drop in the number over the past six months.* In a bid to further counter the spurious drug menace, as of next month, India has also made it mandatory for all pharmaceutical exporters to send their shipments under a trace-and-track surveillance system.

The move will not only pose a hurdle to domestic spurious drug manufacturers , but will also counter drug manufacturers in countries like China who pass off their fake medicines as Indian products. A sizeable number of fake drugs seized in the other countries carry a ‘Made in India’ label, though there is ample evidence that they could be actually made in other countries.

The European Union has also decided to not seize Indian drug dispatches that use Europe as a transit point. According to a new understanding between India and the EU, none of the customs authorities in the 27-nation EU bloc will confiscate any drug dispatches meant for third country destinations like Latin America or Africa. Earlier, some of the EU customs authorities, mainly the Netherlands and France, had confiscated several Indian off-patent generic drug consignments going to Brazil via European ports over alleged infringement of EU intellectual property rights (IPR). Protesting the action, India and Brazil filed a case against the EU in the World Trade Organization. Though this case is related to alleged infringement of IPR, it brought to the fore the issue of sub-standard drugs. Indian pharmaceutical exports total about $10 billion per annum, comprising mainly generic drugs. The government wants to raise these exports to $25 billion over the next three years. Actions like the seizure of drug consignments in the EU ports or charges of sub-standard drugs imported from India can well derail the whole process.

In its continued effort, the government has appointed Karnataka drugs controller B.R. Jagashetty to spearhead a sub-group on spurious and adulterated drugs. The group will support the Task Force constituted to formulate a long-term policy and strategy for strengthening the drug sector in the country.
The government also plans to provide financial assistance to small drugmakers to upgrade their manufacturing plants to World Health Organization standards, effectively tackling the root of the problem.

* Through a special congressional appropriation in the 2008-2009 federal budget, the FDA was given funds to open a series of permanent liaison offices abroad. These include two in India, located in Mumbai and New Delhi. The others are in China [Beijing, Shanghai, and Guangzou] Latin America [Santiago, Mexico City and San Jose, Costa Rica], Africa [Pretoria], the Middle-East [Amman] and Europe [Brussels].

The new “Office of Drug Security, Integrity & Recalls (ODSIR)” will “take the lead in dealing with issues such as supply chain security, counterfeit and diverted drugs, economically motivated adulteration, import operations, and drug recalls,” Woodcock wrote in the memo. Organizationally, the ODSIR division will be housed along with three other divisions under the Office of Compliance. As a result, the Office of Compliance will be turned into a “Super Office,” meaning it houses subordinate offices.

Woodcock tapped Deb Autor, director of the compliance office, to lead the super office. Autor is behind FDA’s efforts – beginning in 2006 – to eradicate unapproved products from the market.

“The drug industry we regulate has become a global enterprise, and our mission of ensuring the safety, quality, and integrity of drugs for the American people has become an increasingly complex challenge,” Woodcock wrote in the memo.

Sanofi has agreed to pay $74 a share for Genzyme — totalling a $20.1 billion upfront payment. But the CVR could boost the payments to Genzyme’s stockholders by up to $14 a share, dependent, largely, on Lemtrada becoming an MS blockbuster. Sanofi is backing this outcome — it says the drug has the potential to achieve annual sales of up to $3.5 billion — but the CVR, said CEO Chris Viehbacher in a press conference call announcing the deal, “was an extremely important tool to bridge differences in value.”

Sanofi will pay $1 per CVR if Lemtrada wins US approval, which the company expects will happen in the second half of 2012; increasing amounts of dollars-per-CVR depend on it passing various sales milestones. Lemtrada is currently in Phase III in the US. A Phase II trial of 334 people with early stage, active relapsing remitting MS, conducted over a three-year period in Cambridge, UK, reported in 2008 that the drug led to a 71% reduction in disability progression in participants (compared with those taking beta-interferon) and a 74% reduction in the relapse rate per year. On average, participants also experienced an improvement in disability at six months that was sustained for the three years.

But Lemtrada’s path to ‘blockbusterdom’ is far from certain. The side effects reported in the Cambridge study included a high rate of (mainly respiratory or urinary tract) infections (affecting 66% of participants). Around 30% suffered from thyroid disorders and there were six cases of immune thrombocytopenic purpura (ITP). Speaking to Bloomberg, Howard Weiner, of the Brigham & Women’s Hospital in Boston, said Lemtrada “is a theoretical cure, but to know that you need to follow people for 10 years. It’s a very strong drug and has potential side effects.” Phil Nadeau, an analyst with Cowen & Co.  (New York) added: “We think the side-effect profile is going to relegate [it] to later lines of therapy,” predicting “relatively modest peak sales estimates,” of $500 million to $1 billion.

Although the number of new MS therapies on way is showing that the basic science of innovation is working, the unknown side effect profiles potential in all these drugs show that the transition from bench to actual bedside is harder than ever.

The Multiple Sclerosis Activism Foundation has also expressed concerns about Lemtrada’s role in the Sanofi-Genzyme deal and what it might mean for subsequent pricing, saying that “for it to be used as a possible treatment for MS, and for Genzyme to be using this as leverage for a higher asking price, is… in our opinion, shameful considering the price of Campath, aka Lemtrada.” Campath, MS Activism goes on, “now sells for $30,000 for leukaemia treatment. But MS patients need only a fraction of the dose used in cancer patients. At the current price, MS patients could get Campath for $7,000 or so. That’s far less than other MS treatments.” But what would stop doctors from using the cancer-priced vials rather than the far more expensive MS priced vials, the group asks — could this have anything to do with rebranding Lemtrada “to make us think it isn’t a cheaper drug?”

The CVR aspect of the Sanofi-Genzyme deal, of course, reflects some of these uncertainties, despite Sanofi’s optimistic pronouncements of Lemtrada’s sales potential. But with both companies putting most of their eggs into the Lemtrada basket, there is a danger some of it could end up on their faces.

Against a backdrop of new figures detailing the mounting cost of fighting cancer, Pharm Exec’s sister CBI conference unit held its annual meeting — co-chaired by Alison Ayers of Pfizer and Ben Steinmetz of GSK — on trends in price, reimbursement and access to oncologics in Philadelphia on January 20-21. Here are a few highlights:

o    Latest data from the National Cancer Institute [NCI] published last month project that the US will spend $173 billion to treat cancer in 2020 – a 39 per cent increase over 2010.  New technologies will drive the bulk of these costs, with treating breast and prostate cancer rising the highest due to the positive impact of these new tools in prolonging survival among patients. Participants questioned some of the assumptions behind the spending projection, noting that growing resistance among payers to pricing of cancer medicines had not been factored in.

o    The era where pricing and access were simply left to the discretion of the manufacturer is over. The major precedent cited is the CMS National Coverage Assessment for the anti-cancer vaccine Provenge. The NCA discourages traditional options in pursuing broad off-label use; guidelines and other access control methods will foster strict observance to the label indication alone.   In addition, risk-based contracting is starting to take root here in the US, with the private-sector [US Oncology] taking the lead.

o    Regulatory hurdles are mounting and the climate for reimbursement and access long-term is unpredictable. The recent FDA decision  involving withdrawal of a marketing license for Avastin as first-line treatment for breast cancer indicates that for many future cancer therapies “fast track” approval will only mean contingent approval.  The prospect of a periodic, rolling process in maintaining license rights means that more monies must be invested in “robust data” which in cancer will mean clear evidence of an increase in overall survival rates, compared to existing therapies.   The content of related REMS commitments will also assume far more importance – getting the right terms that work for clinicians and patients as well as the patent holder will be critical to success.

o    The Avastin case is not an exception – increasingly it will be the rule. According to CBI conference speaker Carol Marchione, some 5 other cancer drugs now on the agenda at the next FDA Oncology Drug Advisory Committee on February 8 are going to face evaluation using similar parameters and thus could confront restricted indications going forward.

o    Companion diagnostic and assays that link cancer drugs to personalized therapy is no panacea to the cost challenge.   Although Roche has broken some ground in this area, several speakers emphasized their utility remains “largely unvalidated, “ not only by the industry itself but especially by regulators.  The FDA has not defined a pathway that is clear on how clinicians – let alone payers – should use such tests and a consensus on this among stakeholders is “at least ten years off.”  There is also the prickly issue of the adequacy of tissue samples required to conduct the tests and the consistency of standards that can validate them.  In the interim, diagnostics are likely to serve only as an adjunct that in some cases can strengthen the value proposition – but is that enough the justify the expense?

o    An issue the industry must focus on is the absence of good comparative, cross-market information on the incidence of cancer in key emerging markets.  The Globocon database administered by the Lyons-based International Agency for Research on Cancer [IARC] is acknowledged as sketchy and riddled with gaps and inaccuracies.  Until the information base improves, drug companies are forgoing opportunities for real market growth in these countries because the public health implications of improved cancer treatment cannot be quantified.  It also complicates pricing decisions in markets where there is a diverse payer base that needs to be segmented to maximize ROI.

o    A panel of payers was asked what they thought should be the drivers of good pricing practices three to five years from now.  Their wish list?

1.    Better evidence from industry on which drugs really work, particularly in moderating the huge hidden costs of side-effects.

2.    More consistent and widespread application of clinical practice guidelines that require use on the basis of the official label indication.

3.    Improvements in randomized clinical trial design, with end points centered on demonstrating real improvement in overall cancer survival rates.
4.    Efficient ways to track and capture pharmacy utilization, at the point of purchase, in turn reducing reliance on high-overhead claims brokering and prior authorization activities.

5.    As the pipeline for cancer drugs moves more toward oral agents, effectively managing the supply chain to reduce the perverse incentives around fixed co-pays and “pill filling” not linked to patient needs.

6.    Defining a societal consensus on managing end of life issues.

There’s no question, of course, that pharma is still being hesitant when it comes to actually engaging with social media, regardless of the desire to do so. Faceoff participant Bruce Grant, SVP, Strategic Services, Digitas Health, advises that it’s helpful “for us as marketers to think of social media not as a channel but as a conversation.” But, he adds “a conversation is not a natural instinct for a marketer, it’s learned behavior.” Currently, it seems pharma marketers main hesitancy stems from uncertainty of operating in a world where “marketers are no longer in sole control of the conversation.”

So will the FDA smooth the way with more guidance on social media? Jennifer A. Colapietro, Partner, Pharmaceutical and Life Sciences Advisory, Pricewaterhouse Coopers, doesn’t think so.  FDA hearings are only likely to result in guidelines and perameters and provisions, she says, “but the rubber really hits the road in your individual interpretations, and operationalizing those within your organization.”

So what can pharma do? One thing is to gain a proper understanding of what social media is. “There’s a common misconception that social media is just the triumvirate of Facebook, Twitter and YouTube. That’s not what social media is,” says Colapietro. “There needs to be some awareness and education about what it is, what the risks are and how you can use it.” Tune in here to find out more!

The first of this new Pharma Faceoff series is already generating some positive responses from industry. Steve Woodruff, President of Impactiviti, says on his blog: “Kudos to Pharm Exec for taking it on… let’s face it – video is where it’s at for on-line communications, and this is a great way to hash out some issues and gain needed exposure.”

Watch this space for more Faceoffs to come.