February 22, 2012

Posts Comments

You are here: Home / Archives for Bloggers / Patrick Stone

Former Inspector Dissects FDA Trial Guidance

February 16, 2012 By Leave a Comment

Patrick Stone, President, TradeStone QA

Alternative monitoring is here. We’ll provide the facts first, and then a little advice.

Sponsor’s of health care products conducting clinical trials for biologics, devices, or drugs, have just been provided with novel approaches to monitoring thanks to the FDA. The agency defines monitoring as “the methods used by sponsors of investigational studies, or CROs delegated responsibilities for the conduct of such studies, to oversee the conduct of and reporting of data from clinical investigations, including appropriate investigator supervision of study site staff and third party contractors.  The primary focus should be on the processes that are critical to protecting human subjects, maintaining the integrity of study data, and compliance with applicable regulations.  The findings should be used to correct investigator and site practices that could result in inadequate human subject protection and/or poor data quality. “ This is a direct quote from the important draft guidance issued in August of 2011 “Oversight of Clinical Investigations A Risk-Based Approach to Monitoring”.

The prerequisite  to implementing and alternative monitoring plan in your project trial master file is the use of all electronic study documentation.  Study documentation includes e-patient source records, e-case report forms, and scanned regulatory records.

Those are some of the key facts. Now here’s some helpful advice.

The cost for using e-records is high up-front, however savings may come with the use of alternative monitoring. Human clinical trials can be monitored remotely from a desk.  The alternative monitoring plan must be  approved by your respective review division up front.

The risk-based approach to monitoring should focus on the most critical data points to ensure subject protection and overall study quality.  Sponsors may be able to monitor the conduct of clinical investigations more effectively than routine visits to all clinical sites and 100% data verification.

This FDA draft guidance was issued to clarify risk-based monitoring with the use of centralized monitoring and technological advances. There may always be a need for on-site monitoring at the beginning, middle and end of a clinical trial which may be more cost effective than going to your site every month. The FDA expects you to tailor your monitoring plan to fit your projects needs and meet the code of federal regulation.

Centralized monitoring and monitoring plan expectations have also been clearly defined in this draft guidance with the option to delegate Sponsor requirements to a contract research organization (CRO).

FDA has also provided clinical investigator training strategies to ensure human subject protection and data integrity. Sponsors & CRO’s are requested to mentor and train study site during the monitor visit. Providing written feedback and reports are a crucial element for compliance with patient safety in mind.

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

TwitterFacebookDiggDeliciousTechnorati FavoritesEmailPrintFriendlyShare
Filed Under: FDA Regulated, Medical Devices, Patrick Stone, Pharma/Biotech, Regulatory Tagged With: , , , ,

FDA Provides Important Clinical Trials Guidance

January 25, 2012 By Leave a Comment

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.

The three main concepts in this risk based approach are:
  1. Subject protection
  2. Human subject rights, and
  3. Data integrity.

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.

For clinical trials the FDA designates three tiers of data:
  1. Data entry
  2. Data review (PI or monitor)
  3. Data processing including transfer to FDA for your application.

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 is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.
TwitterFacebookDiggDeliciousTechnorati FavoritesEmailPrintFriendlyShare
Filed Under: Bloggers, FDA Regulated, Featured, Medical Devices, Patrick Stone, Pharma/Biotech, Regulatory Tagged With: , , , ,

2012 Crystal Ball Predicts a More Aggressive FDA

December 15, 2011 By Leave a Comment

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.

FDA logoDomestically, 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.

 

TwitterFacebookDiggDeliciousTechnorati FavoritesEmailPrintFriendlyShare
Filed Under: FDA Regulated, Food, Medical Devices, Patrick Stone, Pharma/Biotech, Regulatory Tagged With: , , , , ,

Obama Executive Order on Drug Supply Misses The Point

November 14, 2011 By Leave a Comment

Patrick Stone, President, TradeStone QA

The Obama Administration’s recent Executive Order Reducing Prescription Drug Shortages states that some health care providers may hoard drugs that are in short supply.

I am wondering how this is possible if the drugs are not even available to hoard? In this Executive Order it specifically states that root cause analysis and solutions may be out of FDA control. Only the US Congress may appropriate funds for HHS/FDA work force initiatives.

According to the Executive Order, pharmaceutical manufacturers are requested to report timely drug manufacturing discontinuances. But the order clearly misses some important points. The problem is that FDA already knows about drug discontinuance when they order a hold on product or issues a 483 for GMPs with a warning letter follow up.

Moving drug manufacturing out of our country further compounds this drug shortage. It may take years for a drug firm to re-start operations after a move from the US. The fact our US government gives incentives to big drug manufacturers to leave the US with huge tax breaks is also part of this problem.

Generic Drug TabletShipping drug manufacturing to India and China for cultural exchange or to bring up the standard of living is a slow process filled with FDA/GMP regulatory pitfalls. Expedited regulatory review must take place where the pharmaceuticals are manufactured, many of which are overseas.

I am not sure how this is possible when most of the FDA’s funds are already earmarked for FSMA food priorities and congressional mandates. I do applaud Sec. 4 mandating the FDA to communicate with the US Department of Justice (DOJ) on price gouging and hoarding to seek enforcement actions. I am still wondering how hoarding will be possible if the drugs in short supply are not available at all.

This short and sweet Order will hopefully prod the US Congress to address this problem with the full force of the US constitutional authority. Time is a luxury factor we do not have. As I stated before in a previous blog, the pharmaceutical industry and FDA must collaborate to mitigate further risk to national security.

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

TwitterFacebookDiggDeliciousTechnorati FavoritesEmailPrintFriendlyShare
Filed Under: Featured, Patrick Stone Tagged With: , ,

Former FDA Inspector Calls for Increased International Inspections

November 3, 2011 By Leave a Comment

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.

FDA logoUnfortunately, 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.

TwitterFacebookDiggDeliciousTechnorati FavoritesEmailPrintFriendlyShare
Filed Under: FDA Regulated, Food, Medical Devices, Patrick Stone, Pharma/Biotech, Quality Management, Regulatory Tagged With: , , , , , ,

FDA Works to Balance Domestic Drug Supply and Market Freedom

October 6, 2011 By Leave a Comment

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.

TwitterFacebookDiggDeliciousTechnorati FavoritesEmailPrintFriendlyShare
Filed Under: FDA Regulated, Patrick Stone, Pharma/Biotech, Regulatory Tagged With: , , , ,

FDA Policies Contribute to Serious Domestic Drug Shortage

September 19, 2011 By 3 Comments

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.

Generic Drug TabletIt 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.

TwitterFacebookDiggDeliciousTechnorati FavoritesEmailPrintFriendlyShare
Filed Under: FDA Regulated, Patrick Stone, Pharma/Biotech, Regulatory Tagged With: , , ,

Quality by Design (QbD) Pilot Presents Industry With New Challenges

September 7, 2011 By 2 Comments

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.

Generic Drug TabletThe 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.

TwitterFacebookDiggDeliciousTechnorati FavoritesEmailPrintFriendlyShare
Filed Under: FDA Regulated, Patrick Stone, Pharma/Biotech, Quality Management, Regulatory, Risk Management Tagged With: , , , ,

FDA Protects Us From Terror of Unpasteurized Milk

August 8, 2011 By 5 Comments

Patrick Stone, President, TradeStone QA

I don’t know about you, but I sleep easier now knowing that our FDA has declared war on unpasteurized milk in America! It is not enough the US Government is fighting the war on terror (oxymoron) in dozens of countries, the war on drugs, the war on cybercrime, and now the war on unpasteurized milk. Yes, our tax dollars are hard at work, ladies and gentlemen.

For those just joining us, the results so far of these wars is economic collapse. Small business is the only hope for America now otherwise we might as well sign our souls to whomever owns our debt.

I am not sure that unarmed Amish & Quakers or any milk guild selling unpasteurized milk & cheese should be “taken down” with automatic weapons at the ready.  These are Americans trying to make a living.  FDA should educate food producers or show proof positive that adverse events/deaths have occurred from their dairy farm’s product — then go in without the guns blazing. Check the Constitution: innocent until proven guilty still applies.

Raw MilkAs a former inspector, I understand and did my duty when individuals knowingly caused harm or by acute negligence caused harm to another human.  But I feel ashamed to be associated with the FDA with this brand of overkill.

The burden of proof is on the government to show willful harm to the public.  I have not seen the “bodies stacking” up from individuals drinking unpasteurized or blending raw eggs into a protein drink.  An estimated 9 million individuals choose to drink raw milk each year with low ill effect (estimate by CDC, May 2011).

The CDC is a branch of HHS and tied to FDA; why are they on opposite sides of the table on this issue?  This is waste and politics at work with numerous health related issues causing death and disease waiting for FDA’s attention.  What is the real problem (Milk lobby)?

I do not condone “risky” behavior, however this is America and we can choose to live on the edge for freedom of choice.   How about making the consumer sign a waiver noting that they’ve been informed about the possible dangers and let them choose?

The possible dangers associated with consuming milk that is unpasteurized depend on the age of the consumer.  Vulnerable populations are susceptible to bacteria and viruses found in unpasteurized milk.  How do we know these individuals purchasing the “bad milk” are not heating or cooking this milk before consuming it.  The market sells many raw foods meant for cooking and there are many ways to get food regulation compliance.

Work with the market FDA, it’s your duty.

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

TwitterFacebookDiggDeliciousTechnorati FavoritesEmailPrintFriendlyShare
Filed Under: FDA Regulated, Food, Patrick Stone, Regulatory Tagged With: , ,

Here’s Your Chance to Weigh in on FDA Compliance Focus

July 27, 2011 By Leave a Comment

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.

TwitterFacebookDiggDeliciousTechnorati FavoritesEmailPrintFriendlyShare
Filed Under: FDA Regulated, Patrick Stone, Pharma/Biotech, Regulatory
« Older Posts