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FDA finds Indian drug maker Wockhardt hid failed tests

MUMBAI | BY ZEBA SIDDIQUI

Indian drugmaker Wockhardt hid the results of failed tests and deleted data from its systems at a plant in western India, according to a report by the U.S. Food and Drug Administration sent to the company earlier this month and seen by Reuters.

Issues around "data integrity", maintaining accurate and consistent databases, are key to the U.S. watchdog, which regulates the world's largest market for generics producers.

Wockhardt is the latest of several major players in the $15 billion Indian drugs industry to be hit by U.S. regulatory action over the past few months.

It makes around a fifth of its $670 million in annual revenues from the United States and had said the Shendra plant, the site that prompted the FDA report, would boost its U.S. business. Shendra makes lucrative injectable medicines, which analysts say are key to Wockhardt’s U.S. plans.

Wockhardt did not return several telephone calls and emails requesting comment on the detailed report.

The FDA did not immediately respond to a request for comment on its report. It issues such reports, known as a 'Form 483', when its staff believe that conditions at a manufacturing site could lead to products that are harmful to human health.

In the report, dated Jan. 12, the FDA said that among other violations, the audit showed that the results of 22 failed tests had not been recorded. It also found multiple data files had been deleted from some machines.

The FDA did not detail whether the files or tests related to specific drugs, or whether the violations could impact the quality of medication produced at a plant which still exports to Britain and Ireland.

FDA inspectors also reported finding pharmaceutical ingredients that were not stored or labeled properly. A rejected drug batch was stored in the "approved material" area, and some batches did not carry expiry dates, the report said.

Citing his “extensive ties to the pharmaceutical industry,” Senator Bernie Sanders has placed a hold on the nomination of Rob Califf to be FDA Commissioner.

What are those “extensive ties?” Working to design and field innovative clinical trials for FDA review. You want the best and the brightest to work with industry on such matters – because industry is the one that does them. Not academia. Not NIH. Not physicians. And not the FDA. The pharmaceutical industry. And well-designed and executed clinical trials provide important insights into the benefits and risks of potential new therapies. To those reading this column this isn’t a surprise – but to many others it is.

If Senator Sanders thinks that having one of our nation’s keenest clinical trial design experts working with industry is a reason to place a hold on his nomination, then it’s time for him to step back and reconsider his position. When it comes to clinical trials that investigate safety and efficacy, we can't afford to use only the second best and almost brightest.

Yes, Bernie has other things on his mind at the moment, but facts as pesky things.

Somewhat different (but similar) from the FDA's "Filgrastim SNDZ" naming decision, the World Health Organization has posted a final version of its proposed biologics naming policy. It proposed that each biologic, including biosimilars, would be assigned a four-letter “biological qualifier” (BQ) that would make it possible to trace the compounds globally. BQs could be used for pharmacovigilance and to facilitate transferring prescriptions among countries.
WHO would generate BQs. The qualifiers would consist of random consonants, would be separate from non-proprietary names, and could be assigned retrospectively or prospectively.

It's BQ IQ.

A new report by the Pharmacy Benefit Management Institute (PBMI) makes some very interesting points about the value of PBMs to employers and employees. Some highlights include:

* PBM generic copays are in line with overall inflation, only increasing from $9.85 to $10.85 over a 15-year period in inflation-adjusted dollars.

* Preferred and non-preferred brand copays (preferred brand from $19.43 to $31.08 and non-preferred from $37.58 to $56.65) have outpaced inflation considerably.

* Plan sponsors increased use of prescription drug benefit deductibles by 157% in 2015 compared to 2014.

* In 2014, only 14% of plan sponsors reported having a deductible for prescription drugs compared to 36% in 2015.

* There is considerable opportunity for employers who are willing to implement additional strategies to control costs and utilization without shifting additional costs to members.

* Mail order in particular can save members an average of over four monthly copayments per prescription per year (annualized). For a member taking a preferred brand in a three-tier plan design, this equates to yearly savings of $138.88 for a single maintenance medication.

The complete report (sponsored by Takeda Pharmaceuticals) can be found here.

In his Forbes.com blog David Shaywitz comments on an editorial in the New England Journal of Medicine (NEJM), written by editor-in-chief Jeff Drazen, along with Dan Longo. "that a new class of research person will emerge—people who had nothing to do with the design and execution of the study but use another group’s data for their own ends, possibly stealing from the research productivity planned by the data gatherers, or even use the data to try to disprove what the original investigators had posited. There is concern among some front-line researchers that the system will be taken over by what some researchers have characterized as “research parasites.”

Shaywitz writes he was delighted to see the editorial:

"Not because I agreed with it–my heart is truly with the data scientists–but because I was grateful that someone had the courage to articulate a perspective I’ve come to believe is shared by the vast majority of academic researchers, but publicly voiced by no one–until now.
The result: a classic case of stated preference vs. revealed preference, where every academic researcher dutifully claims to be interested in sharing their data widely and freely, but somehow, tend not to actually do this."

David is right.  But there is even more reason to ‘cheer’ the NEJM article.  It reveals that scientist think it is “their” data when in fact it is the patient’s data.  The researcher is entrusted with that data by us to use it to advance science and promote cures. 

And the self-interested way such data is used – or shared – often abrogates the social contract in many ways.

Let me focus on one in particular, from the research article in the NEJM -- CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer -- that was the subject of the editorial.  The researchers used data collected from cancer patients by the National Cancer Institute.  Drazen and Longo call this “symbiotic collaboration.”   I would call it another permutation of an approach that betrays patients. 

The article notes: “Given the exploratory and retrospective design of our study, these results will need to be further validated. We advocate for these findings to be confirmed within the framework of randomized, clinical trials, in conjunction with genomic DNA sequencing studies.”

In other words, the symbiotic collaboration first and foremost will be used to fund randomized trials and sequencing studies support by the same programs that were paid to put together the tissue bank.  As Stuart Kauffman, Colin Hill, Sui Huang and Lee Hood have noted: the methods used to generate so-called evidence-based medicine -- the basis for medical practice and reimbursement—randomized clinical trials (RCT) and comparative effectiveness research—are dangerously broken.

Data-sharing that respects the needs and hopes of patients is defined by how broadly data is shared and the degree to which researchers use data to tailor cancer treatment combinations to achieve the best outcomes possible.

So by definition, companies that use data from a variety of sources to establish biomarkers independent of the researcher who extracted tissue from patients in single person trials and based on powerful machine learning derived algorithms are supporting mutualistic relationships. 

Researchers that boldly push for the Drazen model are, in my opinion, the true data parasites.

I think lots of researchers become researchers because they want to change the world for the better.  You can check out the LabTV YouTube channel and see short videos of hundreds of researchers with such an ethos.   The Drazen model merely reinforces the control of a small elite that are both disdainful of people like Eric Topol who is paving the way for a consumer led data revolution and fearful that the transformation means they will be out of jobs.  Lee Hood’s P4 medicine vision is based on collecting and sharing data generated by patient activated social networks.  Would Drazen call Dr. Hood a parasite??


To those who say that sharing will reduce incentives for innovation, just the opposite is true.  Establishing the relationship between molecular insights and meaningful changes in disease progression depend heavily on collaborations that leverage the digitization of biology to its fullest. 

As Shaywitz points out, now that we know the true motives of researchers, we can define the parasite problem and tackle it head on.

CDER House Rules

  • 01.25.2016

The recent mega-storm allowed many of us drugwonks to curl up with a new work of action non-fiction … from the FDA:

Guidance Agenda: New & Revised Draft Guidances CDER is Planning to Publish During Calendar Year 2016

It’s worth perusing in its entirety, but here are a few items to tickle your regulatory palate:

For those of you following the debate over off-label communications

Manufacturer Communications Regarding Unapproved, Unlicensed, or Uncleared Uses of Approved, Licensed, or Cleared Human Drugs, Biologics, Animal Drugs and Medical Devices

The New Gold Standard

Adaptive Design Clinical Trials for Drugs and Biologics; Revised Draft

Meta-Analysis of Randomized Controlled Clinical Trials to Evaluate the Safety of Human Drugs or Biologic Products

Multiple Endpoints in Clinical Trials

The broader sharing of pharmacoecomonic data

Health Care Economic Information in Promotional Labeling and Advertising for Prescription Drugs Under Section 114 of the Food and Drug Administration Modernization Act

And the continuing saga of “Emerging Electronic Media” (aka: “Social Media”)

Internet/Social Media Advertising and Promotional Labeling of Prescription Drugs and Medical Devices – Use of Links to Third-Party Sites

The evolution of discussing risk information

Presenting Risk Information in Prescription Drugs and Medical Devices Promotion; Revised Draft

For the Biosimilar Brotherhood, three things to consider

Considerations in Demonstrating Interchangeability With a Reference Product

Labeling for Biosimilar Products

Statistical Approaches to Evaluation of Analytical Similarity Data to Support a Demonstration of Biosimilarity

Attention NORD Horde

Guidance for clinical Investigators and Sponsors Natural History Studies for Rare Disease Drug Development

Women and Children First?

Measuring Treatment Benefit in Pediatric Populations: Use of Clinical Outcome Assessments

Pediatric Oncology Product Development; Revised Draft

Pregnant Women in Clinical Trials – Scientific and Ethical Considerations

Pharmacokinetics During Pregnancy and the Postpartum Period – Trial Design, Data Analysis, and Impact on Dosing and Labeling; Revised Draft

Phase Fore!

Postmarketing Safety Reporting for Human Drugs and Biological Products Including Vaccines

REMS Assessment: Planning and Reporting

Waxing Generic

Postmarketing Safety Reporting for Human Drugs and Biological Products Including Vaccines

Updating ANDA Labeling After the Marketing Application for the Reference Listed Drug Has Been Withdrawn

General Principles for Evaluating Abuse - Deterrent Properties of Generic Solid Oral Opioid Drug Products

What’s on CDER’s list is interesting … as well as what is not.

2016 is going to be an interesting year.

Markey's Mark

  • 01.25.2016

Senator Edward Markey (D, MA) is using Senate rules to block the nomination of Rob Califf in an attempt to force the agency to rescind its approval of a prescription opioid for children and change its regulatory practices.

Markey, in Boston Globe interview said he is demanding that the FDA agree to reverse its 2015 decision allowing the pediatric use of the prescription painkiller OxyContin. He also wants the agency to commit to convening expert advisory panels to provide advice whenever considering the approval of an opioid drug, and to ensure that the risks of drug addiction and abuse are taken into account whenever the agency considers approving a prescription opioid.

We call Senator Markey’s attention to the FDA’s new “Guidance Agenda” for 2016.

Prominent on the list are plans to release a new draft guidance on: “General Principles for Evaluating Abuse-Deterrent Properties of Generic Solid Oral Opioid Drug Products.”  That’s important.

Senator Markey is rightly concerned about opioids remaining atop the FDA’s list of “must address” items. But his “hold” on the Califf nomination will, if anything, hold back the agency from making progress on this urgent issue.

Turingfreude

  • 01.20.2016

Terrific article in this week’s BioCentury, “Pricing Politics,” by one of our favorite reporters, Steve Usdin.

Here’s the opening paragraph:

Presidential candidates from both parties are tapping into public anger over prescription drug prices and responding by repeating old proposals, like controlling prices or lowering FDA approval standards, that won’t be enacted and probably wouldn’t work if they were put into practice.

Usdin writes about the “corrosive political environment” and “unrealistic prescriptions (aka: Bernie Sanders). He speaks of schadenfreude over our favorite “Pharma Bro” and how the Turing imbroglio has ignited the always-smoldering fire of public discontent over the way the pharmaceutical industry conducts its business.

How to manage this out-of-control Turingfreude? One way is for the innovative pharmaceutical industry to do a better job communicating the value message (I know, this is a recording) and, per Usdin, both PhRMA and BIO are preparing to ramp up their messaging efforts.

This is important beyond the rhetoric of a political season since many states have transparency initiatives that can only be successfully argued through the lens of relentless science and the potency of value.

In recent days Acorda CEO and BIO CEO Ron Cohen has emerged on the biotech’s sector most effective and articulate voice on medical innovation and drug pricing.

Cohen was quoted in several articles on drug pricing (at least he was taken out of context and misquoted).  And yesterday he was part of a CNBC panel discussion on the cost of medicines. 

The headline for the video blares “Rising drug costs only 'getting worse': Expert”

The expert being Peter Bach.  The definition of an expert is a person who has a comprehensive and authoritative knowledge of or skill in a particular area.

Bach first claimed that drugs are 20 percent of health care spending.  Then he every study shows that drugs like Sovaldi are more expensive than the care it replaces.  He then went on to claim such drugs that Sovaldi aren’t a cure because people can get re-infected with Hepatitis C,

Cohen said:

1. Sovaldi is a medical miracle and do ‘really’ cure.   Beating the virus into submission is the same as NOT having the disease.
2. The insurer funded Institute for Clinical and Economic Review (ICER) shows that even at list prices, Hep C drugs are cost effective.  (Other studies come to the same conclusions.)
3. List price is not what drug companies get. Part of that price become rebates to payers and therefore support a whole posse of PBMs, insurers and oncologists (who get 6 percent of the drug cost as a fee for administering them).

As for the the 20 percent claim, Cohen said that the bigger issue is how to reduce the total cost of care overall and increase value.  Who cares if drugs are 90 percent of the cost of a treatment if it leads to more productivity, longevity and lower spending than would be the case in the absence of such medicines?

It was one of the first times that a media outlet allowed a balanced discussion of drug prices.   And when given the chance to respond, Cohen nailed it.

Bach made claims that belied a lack of authoritative knowledge.  






An article by STAT journalist Rebecca Robbins on drug pricing could use a lot of re-editing for balance and depth.  Or maybe should could find another job. 

She contrasts public ‘outrage’ (as represented by some well-dressed protestors)  about drug pricing with an orgy of greedy indifference on the part of biotech CEOs.
”As biotech executives and investors shuttled from meeting to meeting, seeking deals, many dismissed public outrage at the industry as misguided.
Public anger at drug companies is “an abomination,” Ron Cohen, chairman of the big industry group BIO  (my note: you see, even a trade group of small, money losing companies spending billions on medical research is now BIG as in powerful and dangerous), said at the Biotech Showcase. All the talk about pharma profiteering, Cohen said, is “a perversion of reality.”

Which can also describe Ms. Robbins reporting because of what is NOT included. 

She follows Cohen’s comments (which were taken out of context: Cohen actually said that to smear everyone in the biopharma industry as all being “greedy profiteeers” is an abomination and perverse) with context free narrative about drug prices:

“Many drug makers have raised prices in the past year.  And a slew of new drugs have (sic) hit the market with eye-popping price tags: cancer drugs at more than $11,000 a month; cholesterol drugs at more than $14,000 a year. Then there’s Martin Shkreli, the pharma executive who bought up a decades-old drug and hiked the price 5,000 percent, turning himself into a target of nationwide protests before he was arrested last month on securities fraud charges.”

Yes, linking Turing turd Shkreli who used the Daraprim price hike to short biotech stocks for the sake of his own portfolio, is now lumped in with companies developing new and important medicines that save lives, reduces health care costs and increase well-being is now part of the narrative.

Robbins is not alone in this perversion of reality.  The WSJ’ Peter Loftus runs a me-too story that portrays price hikes as disregarding “mounting criticisms of prescription costs in the U.S”

Loftus claims companies “have raised U.S. prices for dozens of branded drugs since late December, with many of the increases between 9% and 10%, according to equity analysts. The increases are on list prices, before any discounts or rebates that manufacturers sometimes provide insurers and other payers.  Some of the increases add thousands of dollars to the cost of already expensive drugs, and come on top of repeated price hikes in recent years.”

Let’s look at the price ‘hike’ in context.  I will limit this discussion to the deceptive way in which prices are used.   I won’t discuss the fact that neither writer discusses the value of new treatments relative to existing therapies for payers and patients.  


Since Ron Cohen , CEO of Acorda Therapeutics,Inc.  is one of the main characters of these stories, let’s look at how Loftus reports on the pricing of it’s main product Ampyra, which is used to help multiple-sclerosis patients improve walking.  Loftus reports that Acorda raised Ampyra’s price by 11% on Jan. 1, to an annual cost of more than $23,650 a patient. 

Ampyra revenues (unaudited) in 2015 were about $ 436 million.  
When discounts and rebates to PBMs etc are taken into account, Accorda will gain only about 60% of the price increase.

That does NOT take into account that Acorda provides 2 months of free drug to people with new prescriptions, through our First Step program. At this point, 75% of all new prescriptions are First Step (and a higher percent of all commercial Rxs, as we are not allowed by law to give First Step to Medicare/Medicaid patients). The 10-K notes that 38-43% of patients respond to the treamtment, so First Step ensures  the physicians and patients have determined that the patient is a true responder before asking the system to pay for the drug.

It also provides a generous PAP program, giving free drug to a significant portion of the population who are uninsured or underinsured
It also provides co-pay assistance so that no commercially insured patient pays more than $40 for an Rx. 
All this an Acorda is not yet not profitable as a company since it is investing 1/3 of net sales n 6 clinical programs for innovative drugs to treat, Parkinson’s, epilepsy, stroke, MS and migraine.

Which means that the money given to PBMs and insurers aren't spent on more R&D.  Yet neither Loftus or Robbins acknowledge that PBMs and insurers pocket the rebated portion of these prices.  Nor do they note that these organizations then force patients pay to up to 30 percent of the price of the drug which is often marked up by insurers and such pharmacy benefit firms as Express Scripts.  Payers know that companies will – after forking over rebates – also pay a big share of the patient’s drug bill.  (Which explains why per patient sales are way below list price in many cases.)  Indeed, Acorda's copay assistance is provided regardless of where insurers price the drug to patients. 

Robbins points to a Senate report claiming Gilead priced drugs so that many people and Medicaid programs could not afford Solvaldi.  In fact, payers were pocketing the rebates and deny access to the drugs.  The Senate report notes a Gilead memo that states: “While many payers responded to these discounts by opening access broadly, some payers have continued to restrict access despite the discounts. “

Moreover, the Senate report, like Robbins and Loftus, ignored the rebates to the states.  A report based on Medicaid data showed that Medicaid rebates for HCV brand medications “typically increased over time and averaged roughly 60% during 2014 across all brand medications.”  

Medicaid requires companies to provide rebates (to states) of at least “23.1 % of the Average Manufacturer Price (AMP) per unit” or “the difference between the AMP and the best price per unit” to commercial payers if that rakes in more rebates.

On average, AMP is 59 percent lower than Average Wholesale Price, the so-called ‘retail’ price journalists like Robbins and Loftus use.  That means the price used to calculate Sovaldi rebates is $49560 per patient.  ($84000 x 59%).  Gilead then provided rebates of 33 percent of that price according to the Senate report.  That comes out to $33205 per person which is a 60 percent cut from retail price.   Which means that drug prices are a vehicle for redistributing income to private and public payers. 

Finally, neither Robbins or Loftus put drug price increases (net price or otherwise) into perspective.  Loftus states that U.S. prescription-drug spending rose 12.2% in 2014, accelerating from 2.4% growth in 2013. But “price increases for protected brands increased spending by $26.3 billion, contributing 8.2% to total market growth on an invoice price basis; estimated net price growth was substantially lower as rising off-invoice discounts and rebates offset incremental price growth and reduced net price contribution to growth to 3.1%.” 

That’s an increase in spending of about $7.1 billion.  Total US health care spending increased by $100 billion from 2013-2014.  So brand drugs were 7 percent of that amount. 

I believe the incremental benefit of this spending is, a Donald Trump would say, huge.  But first things first.  Reporters should not report on drug prices in a context free zone.  Doing so, especially since the factual context is easily available, is a deliberate perversion of reality. 


CMPI

Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

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