August 1, 2015

Will New User Fees Fuel More FDA Inspections?

Patrick Stone

Patrick Stone, President, TradeStoneQA

For FY 2016, FDA is requesting $4.9 billion to support our essential functions and priority needs, which is $425 million above the FY 2015 enacted level.  Of the total funding, $2.7 billion is budget authority and $2.2 billion is user fees.  The FY 2016 increase consists of $148 million in budget authority and $277 million in user fees.

User fee monies come from new health care sponsors applying for FDA approval to speed up the time it takes to get an audit scheduled. The user fee monies go toward FDA operating cost and employee payroll.

This means FDA will be expected to conduct more inspections to meet the demands placed on it by collecting user fee monies – but this idea raises a number of questions:

  • Will FDA be able to increase the amount of clinical trial audits globally in order to keep up with the user fee expectations for audit scheduling?
  • fancyFDAlogoHas FDA increased training for bioresearch monitor training and have trained inspectors ready to meet this challenge? FDA’s focus has been on food and tobacco inspections the last few years. The latest’s initiatives have been focused on compound pharmacies, the drug inspectorate, and the “antimicrobial blitz for use in feed lots & human use for resistance strain reducing strategy.”
  • Will FDA also increase the amount of health care products approved for the domestic market as well?

The drug shortage list has remained at high levels for the past few years and this fast track approval change is definitely part of the mitigation effort. Most of the budget increase comes from private industry and new product developers so the government burden is around one hundred and fifty million (2.7 billion total). We can only hope FDA is able to meet the increased demand for audit increases and is not postponing regulatory oversight due to limited trained staff shortfalls.

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.


Should FDA Get Tougher on IRBs?

Patrick Stone

Patrick Stone, President, TradeStoneQA

The FDA says IRB’s (Investigational Review Boards) are not required to collect a statement of investigator assurance from studies they preside over.

This is troubling. My first question would be how are IRB’s going to assure clinical investigators will abide by requisite 21 code of federal regulations (CFR) and the sponsor approved protocol? How will IRB’s ensure that the protocol they are approving is authorized by FDA for human clinical trials? is a great repository and can be a big help here, but only if it used by the IRB’s and updated in a timely manner. In my day as an FDA inspector [1998] we were trained that IRB’s are FDA’s eyes and ear’s because FDA is not going to get to very many clinical investigator audits. Fewer than one percent of clinical trials ongoing domestically are reviewed by the agency.

That’s why I’m a little worried. Why would FDA abandon a last line of defense for patient safety? I’m not sure why the agency takes this position, but luckily for patients, most IRB’s do hold clinical investigators accountable for all HHS requirements (FDA & OHRP) and even conduct quality audits for a small percentage of the clinical trials they preside over. If 21 CFR is the bare minimum requirement for compliance, wouldn’t additional IRB oversight be a big boost to compliance if FDA is not able to review a much higher percentage of the domestic ongoing clinical trials?

There’s another area of concern: A 2013 FDA guidance states that only sponsors and clinical Investigators need to keep track of financial disclosure documents. Financial disclosure should be reviewed by IRB’s especially institutional IRB’s that can easily verify if conflicts of interest exist for clinical investigators under their review.

But let’s save that topic for the next time!

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.


FDA’s Action Plan Demands Some Industry Action, Too

Patrick Stone

Patrick Stone, President, TradeStoneQA

“The following Pharmaceuticals FY 2015 Action Plan (the Action Plan), developed by the Office of Regulatory Affairs (ORA), the Center for Drug Evaluation and Research (CDER), and the Center for Veterinary Medicine (CVM), is intended to facilitate operational and program alignment as FDA transitions to distinct commodity-based and vertically-integrated regulatory programs with well-defined leads, coherent policy and strategy development, and well-designed and coordinated implementation.

That’s the FDA’s plain Jane version of its 2015 Action Plan. But let’s look at some interesting wrinkles not necessarily contained in the document.

The Pharmaceuticals Inspectorate will change the way FDA inspectors conducts audits and how many audits will be conducted in a years’ time. There are some interesting things to note here: First, the Center for Biologics (CBER) is noticeably not included in this reorganization effort. Second, district offices will not be at the helm when it comes to which drug firms get inspected and how compliance OAI & VAI cases are handled. Third, CDER will be assuming the lead role and Center compliance teams will be responsible for industry corrective action plans.

prescription drugsTraditionally, the district compliance team for the drug company took the lead role in compliance strategy and remediation. But now, the inspectors conducting drug audits will be dedicated and certified to conduct inspections. This will reduce errors and enhance the quality of inspections domestically and internationally. This will also increase the number of observations (483 notice of observations), warning letters, and consent decrees.

When a generalist inspector conducts a drug audit they may miss a system wide failure or process control deviation due to a lack of training. By contrast, when a professional team of inspectors with dedicated drug training for a drug firms system conduct an audit, those same compliance issues are not usually missed. This is a positive step in the right direction however building the new drug teams and training them accordingly will take years.

Quality by design (QbD) implementation is looming so this will also affect the training requirements from a system based approach to a QbD approach.

Don’t be caught off-guard by this new way of doing things. The FDA is making some changes here, and regulated firms need to make sure they understand them.

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.


Former FDA Inspector’s Crystal Ball: Cloudy With a Chance of Inspected Meatballs

Patrick Stone

Patrick Stone, President, TradeStoneQA

The FDA’s “Food Police” will be in full force to secure budget funds for food safety initiatives for FY 2014 as mandated by congress. More than half of the operating funds will be earmarked for food work. International food inspections will surely be a focus area for the coming year. The inspection goals/FTEs will be set low enough for the field staff to meet or exceed expectations. This again will ensure a steady flow of billions for operating costs. In recent years large chunks of the FDA budget were set for new facilities completion and the dreaded infrastructure technology (IT) upgrades which barely seem to keep up with private industry.

Opioid labeling rules newly penned will assist in identifying and tracking legal drugs, however Internet and backstreet sales will continue to plague the market. Insurance fraud is making it easier for mail-order diversion and out right second hand sales of the legally obtained opioids. So until the insurance scams are tapered this effort will only increase operating cost for the opioid manufacturers.

A medical device tax and new user fees will be required for doing business in our domestic market. It seems that every few years the fee structure increases and becomes more complex. Maybe this is part of the reason our health care cost are always going up exponentially. What will they think of next to add to the user fee list?

compounding pharmacyThe agency has issued product specific sterile drug consent decrees and lengthy 483s for cGMP violations across the nation. There are a few sterile drug manufacturers that judging by the 483 wording will be handed consent decrees very soon. These firms are major market shareholders that have had ample time for remediation without compliance. The recalls from these same firms have been persistent all year.

The great 2013 compounding pharmacy blitz and new regulations request for these manufacturers was not so much as shock and even less awe. The faster FDA defines what compounding drug manufacturing is and provides lengthy guidance on how it should not be done in a compounding pharmacy setting, the faster we will see market self-compliance. Compounding pharmacies must recognize themselves as manufacturing entities and adhere to strict USP <797> and 21 CFR 200 standards that are costly.

Compounding pharmacies are the first line of defense when it comes to the drug shortage so they must operate in strict compliance with sterile the drug cGMP systems approach. More patients will have adverse events and possibly die from non-compliant/contaminated compounded sterile drug preparations if the mindset of the manufacturers is not changed. The State board of Pharmacy cannot shield compounders from civil or criminal liability and the FDA may soon have what it needs for implementing jurisdictional authority.

Here’s to an exciting 2014!

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.



Electronic Medical Records: Don’t Feel So Secure

Patrick Stone

Patrick Stone, President, TradeStoneQA

How often do we see HIPAA violations issued because a regulated entity did not secure the electronic records at the hospital and small clinics? Large scale security breaches and, sometimes, the selling of your e-records by various third party sources are in the news. In Massachusetts and New Hampshire an e-record vendor recently admitted to large scale e-record breaches. The FDA has provided some guidance on what is expected for e-records, but no real guidance on security. That may be one of the reasons that so many of the E-Systems I have reviewed meet the minimal requirements but have security vulnerabilities.

The second half of this story will send shivers down your spine, and then make you mad. Your e-records are being sold to insurance companies, debt collectors, and prospective employers. Yes your e-records are for sale to the highest bidder.  The 1996 HIPAA law left provisions for certain entities to access your entire medical record. Some of the stolen or hacked e-records get sold, and that’s terrible of course, but ironically most of the time your e-records are sold it is “legal.” Securing medical e-records comes with a price and even with some of the best security there may still be a breach. In most business models for building e-record systems security is last on the list. Sadly, it doesn’t appear to be much different in the healthcare industry.

So, what’s to be done?

doctor electronic health recordWill it take a 21st century modernization of HIPAA, written almost twenty years ago and before the e-record mandate? Or will we limp along with legislation that is increasingly showing its age?

In our digital age of e-records our security should be insured since we pay for the care we receive. HHS and congress should be focusing on this but they are currently being distracted by advocating or decrying Obamacare.

And speaking of Obamacare, that new law also has some troubling provisions about who is allowed access to your records, and some “interesting” exceptions to those provisions.

But don’t get me started on Obamacare implentation before we deal with HIPAA.

For now we can only trust (read: hope) but not verify who really has access to our medical e-records that are weakly protected by a 20th century law.

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.



FDA Turns Regulatory Flashlight on Compounding Pharmacies

Patrick Stone

Patrick Stone, President, TradeStoneQA

The latest round of 483 notices of observation forms are out and most of the headlines are all about sterile compounding pharmacies in compliance hot water.  The FDA is now specifically targeting sterile compounding pharmacies for compliance and surveillance inspections. The individual State Pharmacy Boards are less likely to shield local firms in the wake of New England Compounding Center. (NECC). FDA has expanded its unhindered self-appointed access to sterile compounding pharmacies. It does not appear that FDA is limiting its inspections to large hospital system operations. The agency also appears to be targeting smaller regional firms, too.

With well over a hundred pharmaceuticals on the shortage list , sterile compounding pharmacies are more critical then ever. The normal size sterile bags are turned into numerous admixtures for many different drugs, which in turn helps alleviate the shortage. For instance, when treating children you have to turn an adult sized sterile drug into a child size dosage for administration; one big bag turns into three small ones. Otherwise only a portion of the large bag would be used on one patient and then discarded. Some of the drugs on the shortage list can’t be manufactured by a compounding pharmacy, but these operations may be able to stretch out some critically short drugs until more supplies may be manufactured.

The citations issued by FDA have very similar tone and compliance issues.

compounding pharmacyFor example, this Texas firm’s 483 from March 2013 is a laundry list of remediations. I don’t mean to single out this firm, because many other firms have similar citations. But this 483 shows that the main agency concerns include preventing microbial, pyrogen, and viral contaminations (maintaining aseptic environment). Operational configuration (enough hoods for amount of admixtures), employee aseptic technique (media fills), and product stability programs were all noted as deficient. Validations were also lacking for environmental monitoring and decontamination procedures. These are all basic cGMP requirements most pharma manufacturing companies spend much of their resources on. Sterile compounding pharmacies operate close to USP 797 standard but fall way short of FDA cGMP requirements for sterile drug manufacturing.  The above listed 483 Web page is from this FDA weblink:

Ready or not the sterile drug compounding pharmacies will now get a crash course in drug manufacturing 101. FDA will continue to conduct surprise audits on medium and large sterile drug compounders and inspect them as they would a cGMP manufacturer. Why would FDA investigators treat a compounding pharmacy like a manufacturer? FDA does not currently have a sterile compounding pharmacy training course; instead, they have a sterile drug manufacturing training course. It is that simple and until there is a distinction or separate training class offered, we will see more of the same. FDA inspectors are trained to use the USP 797 guide but they still inspect the firm using the 7356.002 Compliance Program Guidance Manual (CPGM) for drug manufacturers.

Will this push to regulate sterile compounding pharmacies make the drug shortage better or worse? Will compounding sterile operators invest in the capitol it takes to make a validated aseptic facility with anterooms and appropriate gowning procedures?

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.


Drug Labels: Free Speech Yes, Dangerous Speech No

Patrick Stone

Patrick Stone, President, TradeStoneQA

The U.S. Court of Appeals for the Second Circuit just overturned the conviction of a drug sales representative promoting off label use for a narcolepsy drug that included fibromyalgia, restless leg syndrome and insomnia (use for drug not approved by FDA). The Dec 3 court decision determined that this falls within the realm of free speech and should be protected. So, they overturned the sales reps 2008 conviction of introducing a misbranded drug into the market.

So is it really just about free speech?

Many off label uses for drugs may be similar in nature to the varying disease states. But the indications above could not be more far apart. Narcolepsy is a debilitating nervous system disease where you fall asleep uncontrollably. Insomnia is a state where you can not fall asleep at all.

Free speech should not harm your fellow citizens. That’s just dangerous speech. I don’t think the Constitution intended to encourage that.

Patients may be harmed by off label use of a drug that has not been clinically proven for that specific disease state. The drug companies are making hefty profits to cover more clinical trials to prove more uses for their medical health products. Off label use does may not always capture SAEs related to off label use. The new SAE’s encountered may not be included for addition to product labeling nor does it prove the off label treatment is effective for the “new use”.

Free speech is not free when the consumer purchases a prescription and is then injured by that drug. Far from free, the patient pays a big cost.

It is very difficult for the average patient to prove a specific drug caused them harm unless they are under a clinical trial where blood and urine samples are drawn regularly to keep track of their health.

I am certainly not against new safe and effective treatments, I am against snake oil salesmen touting panacea “cure all” drugs when in reality no such thing exists.

The False Claims Act for off label drug promotion is a very specific statute. It’s there to keep our medical health product manufacturers and innovators honest.

But false claims aren’t the only law being broken by some offenders. These other offenses include: Physician payout for prescriptions, suppressing risk of the treatment, fictitious clinical trials and price fixing.

There are many more schemes involved and here is a link alerting us to many recent false claims payouts that may break the half a trillion mark.

The FDA will appeal the recent court decision, and this may go to the U.S. Supreme Court for final disposition. But the question remains, will we go back to the snake oil salesman of yesteryear or move forward with transparent, safe and effective health care treatments?

Let’s remember why the FDA was formed over a hundred years ago. It’s about protecting the public health. Not about protecting dangerous speech.

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.



It’s Time for FDA, States to Step Forward for Public Health

Patrick Stone, President, TradeStone QA

It’s clear that the FDA should have more compounding pharmacy oversight, but how long will it take them to make other important decisions on public health?

The recent news is troubling.

Example: According to state and federal records, it took FDA approximately 684 days to issue a warning letter that may have saved lives and time. Usually it should only take 90 days for compliance branch local district directors to decide on a firm’s regulatory outcome. The FDA mandates strict 483 fifteen day response letter times and should also be held to a 60 or 90 day turnaround.

As a former FDA inspector, I’ve been there. Some of the cases I was involved with took 24 months to get a final warning letter decision. This is unacceptable because there is a 6 month follow up that should be conducted.

But if regulators give the regulated industry time to make more  lethal products who is to blame? Usually FDA gets local state authorities involved for immediate detention and embargo of harmful products. Each state has unique authority over products made within it’s borders if they are held for interstate trade. The New England region was also involved with the FDA inspections. The state could have stopped many products from interstate trade before the situation escalated.

PharmaceuticalsThe FDA’s initial inspection on this product began in September 2004 and ended on January 19, 2005. In the Dallas district an Investigator would be reprimanded for taking five months on an inspection. It does not take that long to conduct a compound pharmacy inspection or to collect product samples. It usually takes two or maybe three weeks for this type of inspection. Each district has time limits that can be spent on any one assignment. There seems to be a pattern of errors here that could have prevented lives from being lost with much time wasted.

Going forward FDA must adhere to internal timelines for all inspections and final regulatory compliance determinations. State Pharmacy Boards should allow FDA inspections of firms that compound sterile drug products for conformance with U.S. Pharmacopeia (USP) chapter <797> “Pharmaceutical Compounding – Sterile Preparations,” or cGMP’s. Compound pharmacies should partner with FDA in order to insure safe market distribution of approved drugs.

This should not be a regulatory turf war – it’s a matter of public safety. The state should be brought in early and if necessary take immediate detention and hold actions.  This is a tragic learning experience that should be reviewed with rapid corrective action implementation.

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.




Analysis: FDA Must Have More Authority Over Compounding Pharmacies

Patrick Stone, President, TradeStone QA

Compounding pharmacies nationwide have enjoyed the protection of their state Pharmacy Board, or they don’t distribute outside their home state (no interstate sales).  This means that compounding pharmacies do not have to operate under good manufacturing procedures (GMPs) for compounding their drug products.

FDA routinely inspects compounding pharmacies for verification that compounded drug products are for a specific patient prescription and not for a bulk manufacturing process. We need compounding pharmacies to provide safe products because many drugs do not come in the right strength/dosage for children or special needs patients. Many times FDA auditors find that in fact the inspected compounding pharmacy is manufacturing bulk drug product.

Sometimes FDA auditors observe sterile drug product compounding without sterility/environmental controls in place. Historically speaking, since the 1990’s FDA has gone after many compounding pharmacy operations. However,  FDA has been told many times by state judges they have no jurisdiction and ruled in favor of the compounding pharmacy operations. Congress has also shielded compounding pharmacies from FDA review for various reasons including protecting home district businesses from the big bad regulatory wolf.

The problem here is not the FDA. The real culprits are the compounding pharmacies, the State Pharmacy Boards, and Congress. In this case, FDA is doing its job with its hands tied behind their back. I know because I have inspected many compounding pharmacies during my time at FDA and observed first hand how these companies operate.  FDA management always told me to drop it and move on because we could not do anything about these compounding pharmacies.

The New England Compounding Center (NECC) in Framingham, MA, has been tied to over twenty reported deaths and more than 257 patients have had fungal infections following injections of steroids they manufactured.  Between May 21 and September 24, 2012, patients in up to 23 U.S. states may have received injections of products from this compounding pharmacy. This is going beyond compounding pharmacy practice into national distribution of a sterile drug product.

compounded pillsThe NECC has been in the FDA’s radar since around 2002 when they were first inspected and found to be operating out of control for sterile drug product manufacturing. The main point here is that this is only one of thousands of compounding pharmacies across the nation operating under similar assumptions of sterile conditions without Good Manufacturing Procedures controls.

In a time when drug shortages are at a critically high level, compounding pharmacies can help — but are they really helping? If these operations are not following the FDA drug manufacturing regulations, they are not interested in patient safety. They are only interested in distribution of compounded drug products and profit margins.

State Pharmacy Boards should be inspecting firms that compound sterile drug products for conformance with U.S. Pharmacopoeia (USP) chapter <797> “Pharmaceutical Compounding – Sterile Preparations”. The problem with this is that many State Pharmacy Boards do not have auditors trained to conduct this type of audit and instead focus strictly on DEA aspects, pharmacy practice, and business aspects.

The FDA should be able to regulate these companies under strict drug manufacturing laws with the systems approach method of inspection. These companies always claim it will be too expensive to operate under Good Manufacturing Procedures (cGMP) guidelines. Congress is now going to have to decide whether or not to provide FDA with proper regulatory oversight for this type of drug manufacturing operation. Only time will tell if FDA has to keep its hands tied or if public safety measures will be put in place to keep this type of outbreak from happening again.

Let’s hope the FDA gets the authority it needs to better protect the public.

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.


Is the FDA better off than it was 5 years ago?

Patrick Stone, President, TradeStone QA

Ronald Reagan famously asked Americans if they were better off four years ago during a debate with then-President Jimmy Carter. It worked for Reagan, so we’re going to try a variation of it here.

Is the FDA better off than it was four or five years ago?

Another full year of continuing resolutions with no clear budget has passed FDA by and that makes like 4 or 5 in a row. The FDA did get a budget boost for fiscal year 2011 but that will change with this year’s lower planned amount.

How has FDA done this year with respect to inspections in all program areas? Does FDA really deserve lower funds for conducting fewer inspections? The 2011 FDA metrics show the number of inspection going down per year across the board. This lower trend is continuing to drop even as the FDA has more worker bees on staff.

Well, the management side of FDA will always be top heavy, that seems to be inevitable in any government agency. We will have to wait until January or so to get the final count of inspections completed by FDA this year. But until then, it is already clear that many of the new hires from 2008-2009 are feeling the pay freeze crunch and are stuck below journeyman grade of GS-12 so they can not conduct international inspections when they should be.

They are not performing up to standard according to their supervisors and handlers. Working conditions like these breed low morale and sap production.  Despite what some might think, FDA employees are humans and they are like the rest of us: They are motivated by duty, honor, and a stable household income. I should know, I’ve worked with many at the FDA.

But in my humble opinion these newbies need to be given their step increases and trained less on the job and more in the training room. Don’t throw them out in the field without enough preparation.

All the ingredients for failure are in the mix with little success to sprinkle in. The only output from FDA will be lower inspection numbers and more staff turn over. Many new hires have come to me after leaving FDA asking for help starting a small business and I have answered their call.

If FDA supervisors could focus on facilitating inspection reports and employee retention, life at FDA would be much better. Supervisors are doing many other tasks that take away from their core duties as in doing their bosses work. FDA is also using way too many funds on building new offices overseas with little to no space in those offices for inspectors.

These new offices are for managers and administrators, but not inspection staff. The FY13 budget from FDA was paired down to cut out more funds for this type of allocation.

There is also a need to update and streamline computer software and hardware at FDA that is way behind the technology widely used in the industries the FDA regulates. The focus should be on getting investigators the tools necessary for the tasks assigned, but that may be too logical for government comprehension.

FDA can do a better job with the right internal focus but the shotgun approach to reacting after a problem is simply going to give us more of what we are already getting: Inefficient enforcement lacking a strong overarching strategy.

The FDA needs certainty from policy makers and fiscal balance that has not been seen in more than five years.

I hope we don’t ask this same question five years later only to find the situation has continued to deteriorate. The public health deserves better.

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.