Patrick Stone, President, TradeStone QA

In the age of electronic documents and electronic signatures, the FDA is still defining and providing guidance for 21 CFR Part 11 concepts it began in 2003.  It seems we all really need to catch up.

Now that FDA provides small business webinars and blogs about “the most pressing public health issues of the day”, it is refreshing to note that FDA does not deem all electronic records as regulated; however with human clinical trials, most if not all records are reviewable (investigator discretion).

Basic concepts like hybrid records (paper based, e-records) and meta-data (audit trail data-points) should be well defined by now and not mysterious to industry.  Enforcement discretion still applies for most Part 11 electronic review by FDA investigators.

The new risk based approach will need to be well documented and defined before approval is granted by the respective review division.  In 2007, FDA provided the most up to date guidance and current thinking on computer systems used in human clinical trials.

Once you can establish and document these three risk based controls you are ready to begin your clinical trial. The risk based approach continues throughout all phases of your clinical trial.

Companies conducting clinical trials in the all-electronic environment with e-patient source, e-case report forms, and scanned regulatory records may find that costs go down. You have spent multi-millions in assets to implement validated e-systems so now you may use “alternative monitoring” methods for your monitoring controls.

Human clinical trials can be monitored from a desk if your monitoring plan is deemed acceptable to the review division. You do not necessarily have to pay travel expenses for multi-site monitoring anymore. Here is the game changing draft guidance for “Oversight of Clinical Investigations  A Risk-Based Approach to Monitoring” and I have also included the link for the 2012 Small Business webinar “Electronic Source Documentation in Clinical Trials” here.

There’s more to this subject and we’ll revisit it again.

Patrick Stone, President, TradeStone QA

Will 2012 be a Mayan prophecy year of doom and gloom at FDA or will they get the job done for US/global public safety? According to the FDA website, 2012 will be a year of global regulatory operation and enforcement with emphasis on medical devices, drugs, and food products. Will the 2012 budget from congress for FDA provide the necessary funds as supplemented by MDUFA and PDUFA to complete this global mission?

Third party audits may be a new driving force in the completion of this bold global mission as with the European Union ICH mandates. How will FDA review the third party audits and enforce them accordingly?

The growing pains of letting go of the steering wheel may take FDA some time to get used to. Trusting international “accredited” third party audits may take some time for FDA to digest, too. FDA is used to being in the driver seat for all aspects of firm review and enforcement especially for medical devices and drugs. There may be an uptick in regulatory action internationally and some more supply chain shortages in both medical devices & drugs due to expanded review process.

Domestically, FDA will try to inspect the few medical devices & drugs manufacturing firms left within our borders. The focus may be on dietary supplements and food firms in order to meet congressional mandates for the Food Safety Modernization Act (FSMA). I can only hope that FDA mandates better labeling for our food products with strict guidelines on labeling the percentage of that food product which is imported.

According to FDA,”Nearly two-thirds of the fruits and vegetables–and 80% of seafood–eaten domestically come from outside the U.S.”

As consumers we need to be able to make informed decisions about the food we eat and where it is harvested. Processed foods are not labeling the percentage of imported ingredients within their product. FDA should also focus on human clinical research domestically with an emphasis on training inspectors to complete this goal. We may have lost domestic manufacturing for medical devices & drugs — however human clinical trials have not decreased at the same rate.

Clinical trials must be conducted domestically in order for the test article to be marketed in the US. Logic should dictate that FDA review more of these medical devices & drug human clinical trials. Unfortunately political appointees with no FDA experience lead the mission here, so logic and science are not always a driving force. The field investigator can only do what they are told not what is logically necessary to complete the public safety mission.

Crystal balls aside, let’s hope 2012 is a better year for the FDA.

Read more about FDA’s 2012 inspectional and enforcement trends here.

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

Michael Causey, Editor & Publisher, eDataIntegrityReport.com

The FDA has to speed up adoption of a “Benefit-Risk Framework” to improve decision-making in the regulatory process, said John Lechleiter, Ph.D., chairman, president and CEO of Eli Lilly and Company.

Speaking at recent industry conference, the CEO of the drug giant called for a regulatory process that focuses both on recognizing and appreciating benefits while identifying and minimizing risks. Such a balanced approach would help increase the flow of needed medicines to patients and reverse a trend of fewer new drugs getting approved, he said.

“The stakes are high,” Lechleiter said. “The only way to make inroads against [chronic and other] diseases is to sustain the pace of medical progress.”

The FDA appears to be a bit on the defensive here. It recently issued a report touting its record approving drugs it says demonstrates it isn’t stifling innovation at all thank you very much.

The backdrop to this battle is the upcoming reauthorization of the Prescription Drug User Fee Act (PDUFA) V. Originally enacted in 1992, PDUFA and its iterations set the foundation for how FDA will manage the drug review process for five years, beginning in October 2012.

Lilly’s Lechleiter stressed the importance of a non-partisan course for reauthorization. “As a basis for the drug review process, PDUFA is too important to get bogged down in partisan politics,” Lechleiter said. “As Congress considers reauthorization next year, we hope to see a ‘clean’ bill – one free of extraneous and controversial provisions that would politicize the bill and further complicate matters for all parties.”Lechleiter said the regulatory system must continue to evolve to meet 21st century needs.

Lechleiter offered five key characteristics of a “state of the art” regulatory approval system:

1. Timely – “There are far too many conditions for which therapy is inadequate or nonexistent. We need a system that is not only effective, but efficient as well.”
2. Predictable – “The system must be predictable in its judgments, its decisions, and the criteria on which those decisions were based – whether scientific, ethical, legal, etc.”
3. Consistent – “The system must be consistent across review divisions using standardization and repeatable processes – so that an innovator clearly understands the regulatory requirements and so that institutional learning can be harnessed to replace time-consuming one-off learning by review groups and division.”
4. Transparent – “The system needs to be transparent in its judgments and criteria so [stakeholders] understand the rationale for its decisions.”
5. Scientifically rigorous – “This requires scientific expertise within the agency – or access to the expertise – that understands, engages in, and influences the constantly evolving external scientific environment and ensures that standards are up-to-date.”

Lechleiter also discussed ways to strengthen a medicine’s benefit and lower its risk, including calling for greater emphasis on improved outcomes for individual patients, through the development of tailored therapeutics.

“From the point of view of patients and their doctors, a tailored therapy will provide a better benefit/risk trade-off, because they can have a higher degree of confidence that it will work effectively and with minimal harmful side-effects relative to the benefit obtained,” said Lechleiter. “From a value-for-money standpoint, tailored medicines should also reduce the heavy costs associated with non-responders. In other words, payers will get what they are paying for.”

Cry havoc and let slip the dogs of war. This one isn’t over by a long-shot.

Patrick Stone, President, TradeStone QA

Here’s an idea: More FDA inspections outside the US, at a lower cost.

How?

If FDA trained other countries health organizations to conduct FDA business with Memorandums of Understanding (MOU), less money could be used to travel with more inspections completed. This training could be accomplished online and by going out with FDA International Investigators. The EMA should have a MOU if their model is similar to FDA’s. The advent of all electronic review should alleviate the need for more international inspections.

I admit I may be over-simplifying the issues with training monies and bringing foreign inspectors to US training facilities. But I think the basic idea holds water.

Host nations can send their inspectors for knowledge sharing and training with justifiable beneifits to the host nations public health. FDA can also video link for training, as is done currently for new hire training.

Unfortunately, innovative options are scarce at the FDA Senior Executive Service level (SES) and the old way of doing business is ingrained into the government model. For the short term FDA will try to increase international inspections in all program areas with a focus on food work.

I’ve observed many international drug and device firms receiving warning letters and multiple item 483 forms. If this current warning letter trend continues, the blame may fall on lack of FDA regulatory guidance.

The core mission of FDA is to protect the US public from harmful health products. Sending FDA field Investigators to where the products are manufactured and undergo human clinical trials is one of the only ways to accomplish the core mission. Ensuring that field investigators are proficient for the task and seasoned investigators stay engaged will be the challenge.

The international firms with compliance issues should be reviewed by their country’s FDA equivalent for cross training on regulatory compliance.

On the job training is used here at home as a component of new hire training. FDA will have to think outside the box if Congressional Mandates for International travel are to be met.

Congress must also understand that it is not only the amount of funds that insure successful international travel, it is also about proficient field investigators as well.

I have faith that FDA field staff will answer the challenge because they always do.

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

Patrick Stone, President, TradeStone QA

The balance between cost effectiveness and a safe drug supply may be measured in the amount of poor/under-employed patients not receiving their medication. These individuals may seek their pharmaceuticals online from imported sources thus breaking the law and possibly receiving harmful counterfeit drug products. Counterfeit drugs and placebos, labeled as heart medications, blood pressure medications, diabetes medications, etc., are currently hospitalizing a vulnerable proportion of American citizens.

The FDA does not publicly go after counterfeit drug operations and the Office of Criminal Investigations (OCI) at FDA would be responsible for the interdiction of such criminal activity. There are very few OCI agents in the FDA, so counterfeit drug searches are not conducted Sheriff or Texas Ranger style. If the FDA OCI get a tip about a counterfeit operation they usually go in with Sheriff and FBI/DEA/HS for back up.

FDA public affairs and media relations may not go far enough explaining and describing the extreme dangers of buying health care maintenance drugs from an unapproved imported source.

There are many reputable foreign pharmaceutical companies legally and safely distributing effective imported medications. The FDA is currently focused on tobacco and food products like rural milk production; counterfeit pharmaceuticals appear to be low priority. Many of the counterfeit drug operations take place outside the United States and are imported in through legal or illegal channels.

The FDA Import Division would be the most responsible resource for stopping the flow of harmful drug products. The DEA and DOJ are focused on scheduled narcotics and bulk illegal substances. When the product comes in a pill bottle sold in most drug stores the priority may also be very low.

Health-care customers and marketing business firms need to understand the US regulations for importing health-care products from licensed broker that goes through the FDA/US Customs regulatory oversight. It is always good to verify that the product you purchased matches the description on the package insert.

The US government is trying to balance security and freedom of choice on the razors edge. It may take some time to ensure security at the cost of your advertising freedom. It is always a good idea to ask your doctor or pharmacist about your drug products and how to physically identify your medications.

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

Michael Causey, Editor & Publisher, eDataIntegrityReport.com

Under pressure from all sides, the beleaguered FDA keeps announcing new reorganization initiatives, name changes and all sorts of stuff that would be funny if it was scripted by the same team handling Steve Carell’s departure from “The Office” and the ushering in of the new James Spader era.

Unfortunately, in real life these things aren’t always so funny. The FDA has been mocked in many quarters for its failure to maintain a balance between protecting the public safety and encouraging innovation among device and drug companies.

The list of FDA reorg moves made in just the past year would fill pages of old-fashioned newsletter space, but suffice it to say that the FDA has made a lot of changes and shows no signs of stopping.

Question: Should device and drug manufacturers care?

Short answer: Yes.

Question: Do the FDA changes mean more inspections and enforcement action for device and drug manufacturers.

Short answer: Yes.

We’ve spoke with several drug and device company compliance officers in the past few months, and without exception we’re told that dealings with the FDA have become more time-consuming and frequent. Not surprisingly, none wanted to go on the record for fear of further irritating an already irritating (to them) agency.

“I didn’t like the FDA’s approach five years ago, but now I miss those days,” a mid-size device firm compliance officer recently told us, only half jokingly.

Areta Kupchyk

Areta Kupchyk, a partner and former FDA-er now at Reed Smith LLP, notes that “where FDA puts their resources typically reflects their priorities and approach to enforcement.  For example, FDA appears to be putting resources in enforcement areas and giving some of those divisions more independent authority from the chief counsel’s office to take action,” she tells us.

“FDA also wants to speed review times for 510(k) submissions, orphan drug designations, and therapeutic biologics (especially biosimilars).  The new acting Chief Counsel, Liz Dickinson, has a strong background in generic drugs and biosimilars and we are very likely to see more focus in this area,” Areta adds.

These FDA changes are mostly going to impact mid- and small-sized companies on the device side, Areta says. “Large pharmaceuticals already basically understand how compliance works and how to do it, but the mid-size device companies in particular don’t have enough experience with quality systems and GMPs,” especially as FDA’s interests and demands seem to keep changing.

Patrick Stone, President, TradeStone QA

Our domestic pharmaceutical drug shortage situation is a direct result of FDA regulations, FDA reviewer turn-over/project overload and pharmaceutical companies outsourcing production outside the United States.

These three factors are a key part of the current shortage which has many ingredients such as the high cost of conducting business (shipping, labor, tax, and mfg/dist plant overhead). With all of the current pharma mergers and acquisitions, it’s a miracle only 246 products are in short supply.

Those pharma companies that left Puerto Rico and the mainland United States now have to deal with US Customs and the FDA Import Division along with your host nation’s requirements. The low foreign labor cost benefit analysis may not have accurately accounted for shipping supply delays and operating cost over-runs.

FDA, along with the center specific review divisions, have some turn-over and training issues to contend with, too. Maintaining domestic compliance with 21 CFR Drug Regulations through the systems approach with certified drug investigators is proving to be a difficult task for the FDA Districts and Center Departments. The perfect storm conditions have gathered for a serious drug shortage beyond the 246 we currently have on the books.

It is a national security issue when the US has drug shortages of vulnerable population drugs and critical care maintenance pharmaceuticals on the shortage list. The Quality by Design (QbD) system will further compound the domestic and International chemical & biotechnology drug product development cycle. The ability to react to a vulnerable population drug shortage should be the focus — not outdated chemistry manufacturing control (CMC) regulations.

The pharmaceutical industry and FDA must collaborate to mitigate further risk to national security. We all have a major stake in health care continuity and national security.

Sound scientific method without FDA manufacturing micro-management should be the focus. A drug supply contingency plan must be approved by FDA for drug production to react to a major market shortage. Let drug manufacturers put in a market shortage contingency plan for their drug products or let the market figure out the best way to conduct business.

FDA needs to focus on QA and not the business side of the pharma industry.

A final message to the pharmaceutical industry: come back home to the US. There are plenty of truly skilled individuals ready to work, and land prices plus pad sites have generally gone down. Come on down and build your plants in my state of Texas — we are a business friendly state with no state tax.

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

Michael Causey, Editor & Publisher, eDataIntegrityReport.com

A sobering report from the American Society of Health-System Pharmacists (ASHP), the American Society of Anesthesiologists (ASA), the American Society of Clinical Oncology (ASCO), and the Institute for Safe Medication Practices (ISMP) highlights a serious and growing drug shortage problem in this country – and the FDA is one of the big problems, according to many in the drug industry.

“This is a national security and health risk conundrum,” says former FDA reviewer and now industry consultant (and fellow Assurx blogger) Patrick Stone.

“If the pill well runs dry on our seniors or high risk folks they may expire or degrade further in health,” Patrick worries. The FDA’s “GMP controls and tightly held batch quotas are a mess. QbD will add fuel to this fire by doubling the number of drugs that don’t make it to the shelves.”

A distressing article from Marginal Revolution raises further questions about why this is happening and FDA’s role in it. “Currently there are about 246 drugs that are in short supply, a record high. These shortages are not just a result of accident, error or unusual circumstance, the number of drugs in short supply has risen steadily since 2006. The shortages arise from a combination of systematic factors, among them the policies of the FDA.”

Stone’s take: “The FDA simply doesn’t understand how many drugs are impacted by its regulations.” He challenges the agency to track that, just as it tracks 483 violations and other issues.

Editor’s Note: Watch for a new Patrick Stone blog on this topic next week.

Patrick Stone, President, TradeStone QA

What products will be affected by QbD? It will apply to new Marketing Authorization Applications (MAAs)/New Drug Applications (NDAs), Type II Variations/Prior-approval supplements (sNDA) and Scientific Advice requests/CMC formal meeting request that include QbD/PAT elements and are submitted to FDA & EU new applications, for MAAs/NDAs where the sponsor/applicant has agreed to a parallel evaluation by both agencies.

Upon request from the sponsor/applicant, and where procedural time-lines will allow, Type II Variations/NDAs may also be considered on a case by case basis. Right now this is a voluntary pilot with some pharma companies being tapped or nudged by FDA & EMA to join in.

Our geographically diverse health product market involves more contracting and outsourcing for many product components. Finished product real time testing and design space requirements will be crucial for implementing QbD.  ICH third party QA mandates will result from this pilot program.

QbD products will be as unique as the individuals who receive them (personalized medicine). This new model may impact two-thirds of the new health care products in the pipeline (cell therapies, gene therapies, and molecular entity therapy).   There will be many approaches to high order characterization and some are not cost effective at present.  Many of the details will take years to sort out. Collaborations between the FDA, Japan Ministry of Health, and  European Medicines agency will require funding along with mutual scientific trust.

Emerging technologies and laboratory techniques will be required to accomplish the QbD paradigm shift. FDA can’t continue using the chemistry approval model for biotechnology products.  This paradigm shift may increase development times and cost structures.  The ICH model will also bring mandatory third party QA review so prepare your models for this as well.

Here are the essential points to focus on for QbD products:

1. Target the product profile,
2. Determine CQAs (Critical Quality Attributes),
3. Link raw material attributes and process parameters to CQAs,
4. Risk assessment,
5. Develop a design space,
6. Design and implement a control strategy.

The biotechnology sector QbD product development focus will be on design space and real time release testing. The pilot discussion focus for both regulatory agencies will be on ensuring consistent implementation of ICH Q8, Q9, and Q10 guidelines in the assessment process and to facilitate sharing of regulatory discretion & new regulatory concepts manufacturers of small-molecule generic drugs have concerns the initial lag-time in course correcting for the QbD initiative may exponentially delay the application file time for their products.

It appears some generic-drug manufacturers are not willing to implement any QbD concepts until closer to final harmonization and discussion time frames.

Why do you need higher order structure modeling?  Higher order structure product applicants will have to provide protein folding kinetics models with characterization integration into the application and annual report.  Your research models and early development modeling may be progressed for this function. Personalized medicine with batch to batch consistency including stability of 1-90 days is recommended. There are also talking points about including variants and aggregates of your products in the higher order structure models.  Intra and inter chain disulfide bonding, aggregation, and complete polypeptide modeling may be requested application material.

This may prove to be more cost effective while two juggernauts (FDA & EMA) iron out the red tape that will flow from this type of global initiative.  If the funds necessary to make this effort progress are not available on the FDA or EMA, side delays in the process are inevitable.

Molecular and personalized medicine can’t continue to be reviewed with the FDA chemical entity systems approach, approval model.   Effective cancer therapies and molecular medicine may not have the statistical significance necessary when only a handful of patients are treated with the cell or gene therapy.

Warning to Industry: FDA will obviously not let you have your cake and eat it too.  Innovate inevitable change by comments to FDA or accept the QbD change that is inevitable.   Your comments to the FDA will be monitored on the FDA’s Facebook page and current open comment requests. Contact your respective FDA liaison or center contact for discussion points directly related to your product.

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

Patrick Stone, President, TradeStone QA

The FDA is evaluating every regulated program in order to enhance compliance strategy. The drug program is on deck for the enhanced program evaluations and the agency will open the comment period for the next sixty days.

The enhancement in drug regulations will mean new drugs in the pipeline will take longer to get to market and the products on the market will endure post market safety studies for continuing evaluation of safety and effectiveness.

I would recommend drug companies make it clear in their comments that these FDA changes will make life tougher for small businesses and elongate the timetable they work with in getting new products to market.

I think that the already rising cost of health care will skyrocket to new highs when the enhanced drug regulations are implemented. Some of the proposed changes appear necessary but only time will tell what regulations are actually enacted.

That’s why it’s important for industry to weigh in with comments.

Combination therapies will have to include much more safety data or risk rejection from CDER. Animal studies (GLP) will be increased for toxicity and risk benefit.

I have observed that many good laboratory firms are conglomerating and outsourcing to far east partners. But the price of doing business out of country will not be cheaper in the long run. Shipping costs and intellectual loss will have to be factored into the great globalization effort.

Quality by design (QbD) is a pilot project now but its reference in the federal registry heralds the inevitable federal mandate. The actual report for new enhanced drug regulation may be found here.

Big pharma may be able to navigate the new ocean of regulation but what happens to the start-up biotech companies? Your voice counts for the next 60 days and then the new regulation will follow accordingly.

Make sure to follow Patrick on Twitter.