VP CHINTAN BAITHAK GOA 2015: Ananth Shenoy: GENERICS PHARMA PIPELINE BASICS

[crazymama]

Found an excellent summary of the FDA inspection process.
Recommend to visit the source URL for complete read.
http://www.metricstream.com/insights/FDA-inspections.htm

I have collected the important snippets for reference -

WHO DOES THE FDA INSPECT AND HOW OFTEN?
The Food, Drug, and Cosmetic (FD&C) Act gives FDA the authority to conduct inspections at drug and medical device manufacturing facilities, among other regulated types of facilities. The FDA selects companies to be inspected primarily based on risk . Those companies manufacturing drugs and higher risk devices, top the list. Thus, manufacturers of class III devices, sterile drugs, prescription drugs, newly registered facilities, implantable, life-supporting, and life-sustaining devices, are the primary subjects for inspection.

Facilities having historical significant violations, are also FDA inspected.

For pharmaceuticals and the risk based inspection system, FDA focuses on three types of facilities: sterile drug product manufacturers, those that produce other prescription drugs; newly registered facilities that had not been inspected previously ,and focuses on 3 factor categories: Quality and Product Safety; Facility; Process.

As per the Federal Food, Drug, and Cosmetics (FD&C) Act, domestic drug establishments, and Class II and Class III device manufacturers are to be inspected every two years (surveillance). Foreign manufacturers were inspected on an average of every 9 years. However, due to FDA’s budget increase, an increase in manufacturing plant inspections (domestic and international) has resulted. This budget increase is equipping the FDA to add staff and open international offices in major countries . Consequently, foreign inspections, do not have an every 9 year average anymore.

Inspections are also conducted prior to a company acquiring Premarket Approval Application (PMA) and New Drug Application (NDA) approvals, as well as Biologics License Application (BLA) licensing.

FDA QUALITY SYSTEM INSPECTION TECHNIQUE
FDA uses the Quality System Inspection Technique (QSIT) for its inspections. QSIT is based on a top-down approach to inspecting a manufacturer’s QS. The technique provides different inspectional levels based on reason for inspection.

In the medical devices industry, QSIT is used by the FDA to assess the firm’s QS for compliance with the appropriate regulations and for inspection of domestic and foreign manufactures of medical devices intended for commercial distribution in the United States.

The inspection will assess the firm’s systems, methods, and procedures to ensure that the firm’s quality management system is effectively established and maintained. The QS inspection should include the assessment of post-market information on distributed devices.

QSIT Devices Overview

The manner in which QSIT relates to the Pharmaceutical Industry, is through the guidance document: “Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations”. This guidance document defines requirements for all aspects of a firm’s quality structure. Firms that comply with the expectations of both 21 CFR Part 210/211 and QSIT, are aligned to the expectations of the referred guidance.

The Center for Drug Evaluation and Research (CDER) defines and groups QSIT into six major systems which consists of:

THE INSPECTION PROCESS IN A NUTSHELL
Here is what happens on the day of an FDA inspection:
• Receptionist activates the designated alert system.
• Company Inspection Team members go into their roles and designated areas.
• FDA provides the company with Form 482 and identification.
• At opening meeting, FDA explains why they are at your site.
• After a facility tour, the FDA inspection team, requests documents and begin to conduct interviews.
• FDA conducts the Exit Inspection Meeting.
• Findings are reviewed and description provided of any violations/deficiencies from current regulations, deviations from company’s own procedures and further clarification of misunderstandings can be addressed.
• FDA presents Notice of Observations (Form 483) to management and executive management present at exit meeting with annotations (the latter, if both parties agreed to annotations). The 483 lists inspectional observations. However, it does not represent a final Agency determination regarding your compliance.
• Upon return to local District Office, FDA investigator:
o Writes an Establishment Inspection Report (EIR) (normally, they begin writing it right at the firm’s site)
o Forwards report to headquarters and the Agency classifies the inspection
o After headquarter evaluates, you may receive a Warning Letter

WARNING LETTERS
If the inspection has an Official Action Indicated(OAI) classification, the FDA will send a warning letter to the company, describing the manufacturer’s violations of FDA regulations and requesting a reply, usually, within 15 working days after receipt of the letter. In such a case, the company will need to reply using the same format as the 483 response, and including documented evidence of corrective actions.

Usually , FDA conducts a follow-up inspection to verify that the appropriate corrections have been implemented and *are effective.

After the FDA has completed an evaluation of corrective actions via follow-up inspection, it may issue a clo*se-out letter.

A FEW BEST PRACTICES FOR SMOOTH FDA INSPECTIONS
Companies can ensure a smooth inspection process by following a few best practices:
• Have adequately trained resources with relevant expertise and accountability.
• Get upper management’s support on compliance and quality programs.
• Don’t underestimate the value of an independent regulatory compliance team and an expert quality assurance team.
• Make sure you have implemented the commitments made from previous inspection.
• Understand your potential quality data sources.
• Implement and assess an effective QS.
• Invest time, designate accountable resources.
• Ensure there is a designated company Inspection Team.
• Ensure proper documentation and records.
• Maintain effective Management Review and CAPA systems.
• Identify true root causes of issues using appropriate problem solving tools.
• In-bed in organizational culture, proactiveness.
• Understand when a product, or quality issue is significant.
• Have defined metric systems to monitor your QS in order to identify trends, gaps, and opportunities.

LEVERAGING TECHNOLOGY TO PREPARE FOR FDA INSPECTIONS
Both for 483s and warning letters, you will need to:
• Put together a project management team and assign accountability.
• Use change and document control systems, CAPAs and other quality systems to implement and monitor the changes needed and to sustain them.

[crazymama]

Apologies upfront for a long post.

Wanted to slay the “Exclusivity dragon” once and for all.

I will summarize the gist of my understanding based on the collected snippets from various sources mentioned at the end of this post.
• All the patent codes apply to the Innovator’s branded drug.
• All the exclusivity codes, except for PC (Patent Challenge) applies to the Innovator’s branded drug.
• For exclusivity code, PC (Patent Challenge) it comes into effect for the FTF ANDA applicant implying the 180-day exclusivity.
• Exclusivity codes such as NCE and ODE are significant in the respect that they indicate with a high probability that probable FTF ANDA applicant is likely to submit the ANDA at “NCE-1” (i.e. 4 years after NCE approval, and 1 yr before expiry) and notify the Innovator who in turn will initiate the Para IV Litigation.
o Thus, as Ankit indicates in his excellent “Key molecules” reports more often than not the sources for Para IV information is from litigation dockets/research reports. (rather than depending on Exclusivity code which reflects after the fact post the Final Approval)

All the information below are re-formatted and curated from their original sources.

Hatch‐Waxman Amendments

Grand bargain for Brand and Generic Industries
• Brand Industry Gains:
– 5‐year New Chemical Entity (NCE) Exclusivity
– 3‐year New Clinical Studies Exclusivity
– Patent Term Extension to account for time patented product is under review by FDA
• Generic Industry Gains:
– Ability to challenge brand drug patents prior to marketing in court
– 180‐day Generic Drug Exclusivity

What brand must do: “list” patents
• NDA sponsor must identify in NDA those patents reasonably related to drug product, drug substance, or method of using drug for which approval is sought.
• FDA “lists” patents identified by NDA sponsors in “Orange Book” (OB).
• NDA referred to as “reference listed drug” or RLD.

What generics must do: “certify”
• Certify with respect to each patent listed for that RLD in the OB:
• patent information has not been filed (“paragraph I certification”) = FDA can approve ANDA when ready
• the patent has expired (“paragraph II certification”) = FDA can approve ANDA when ready
• the date the patent will expire (“paragraph III certification”) = FDA can approve ANDA when patent expires and ANDA is ready
• the patent is invalid or not infringed by the drug product proposed in the ANDA (“paragraph IV certification”) = complex approval landscape

What follows from PIV certification
• After FDA notifies applicant that ANDA is sufficiently complete to review, applicant must notify NDA/patent holder of Paragraph IV certification.
• NDA sponsor can sue when it receives notice.
• Infringement lawsuit can start prior to ANDA approval and marketing
• If NDA sponsor sues within 45 days of notice, ANDA approval is stayed for 30 months.
– Runs from date of notification or expiration of NCE exclusivity
– May be lengthened or shortened by the court
• No lawsuit with 45 days = FDA can approve ANDA when ready

All possible Para IV Outcomes

Tentative Approval
• ANDA ready for approval but blocked by patent, exclusivity, or stay = only eligible for tentative approval (TA)
• Full approval not automatic after TA – must show ANDA still meets requirements for approval at time of full approval,
• TA’d ANDAs must request full approval

180‐day Exclusivity

• Reward for ANDA applicants that challenge patents, potentially hastening generic market entry
• 180‐day exclusivity is only available to “First to File” (FTF) ANDAs containing PIV certification
• Commonly there are multiple FTFs = shared exclusivity for FTF cohort
• Subject to forfeiture

New Chemical Entity (NCE) Exclusivity
– Five year data exclusivity from the date of first NDA approval for products containing chemical entities never previously approved by FDA
– ANDAs with Paragraph IV certification may be submitted four years after regulatory approval (NCE -1), but may not receive approval until the expiration of the exclusivity period

What’s shared exclusivity?
If multiple ANDAs are submitted for the same drug on the same day, the 180-day market exclusivity is shared between the first two generic companies. Actavis (ACT) shared 16 out the total 49 market exclusivities in 2012. To an extent, shared exclusivity diluted the attractiveness of the exclusivity. However, FTFs still holds a charm.

Guidance for Industry 180-Day Exclusivity When Multiple ANDAs Are Submitted on the Same Day, July 2003
180-Day Exclusivity When Multiple ANDAs Are Submitted on the Same Day | FDA
FDA intends to apply a multiple first applicant approach to eligibility for 180-day exclusivity by considering all substantially complete ANDAs, amendments, and supplements containing a paragraph IV certification to a listed patent that are submitted to the OGD document room on the same day as being first applicants, when no paragraph IV certification to the patent has been submitted on any previous day, as long as the applications comply with the applicable requirements for submission. FDA considers this approach to be an appropriate interpretation of the statutory language and consistent with the goals of the Hatch-Waxman Amendments. This approach will provide all applicants submitting patent challenges on the same day an opportunity to share in exclusivity; it permits submission by U.S. mail or courier or delivery service; it permits, but does not require, submission in person; it avoids the random aspect of a lottery or mail room date stamp approach; it will prevent disputes over who’s first, which rely on video and other evidence; and it will preserve the safety and security of the applicants and FDA property and staff.
Consistent with FDA’s current practice, submission by facsimile or email is not considered officially submitted for purposes of determining the date of submission.
The approach to 180-day exclusivity described in this guidance will apply only in cases in which multiple ANDA applicants submit paragraph IV certifications challenging the same listed patent or patents on the same first day. The Agency recognizes the highly competitive nature of the generic drug approval process and the possibility of substantial profits for the recipient of 180- day exclusivity. There is no public health reason to encourage and reward competition over being the first to submit a paragraph IV certification within minutes or seconds of another such applicant. The Agency believes that, where there are multiple filings on the same first day, the multiple first applicant approach is consistent with language of section 505(j)(5)(B)(iv) and with the intent of both the 180-day exclusivity provision and the Hatch-Waxman Amendments.

3. How long is exclusivity granted for?
   It depends on what type of exclusivity is granted.
   Orphan Drug (ODE) - 7 years
   New Chemical (NCE)- 5 years
   “Other” Exclusivity - 3 years for a “change” if criteria are met
   Pediatric Exclusivity (PED) - 6 months added to existing Patents/Exclusivity
   Patent Challenge – (PC) – 180 days (this exclusivity is for ANDAs only)

4. Why does the exclusivity expire before the patent?
   Patent before exclusivity?
   Why does a particular drug product only have patents?
   Only have exclusivity?
   Have neither?
   • Patents can be expired before drug approval, issued after drug approval, and anywhere in between.
   • Exclusivity is granted upon approval of a drug product if the statutory requirements are met.
   • Some drugs have both patent and exclusivity protection while others have just one or none.
   • Patents and exclusivity may or may not run concurrently and may or may not encompass the same claims.
   • Exclusivity is not added to the patent life.
   • Expired patents and exclusivity are not included in the published list.

Forfeiture of FTF 180-day exclusivity

In December of 2003, the passage of the Medicare Modernization Act included the Forfeiture provisions. The MMA identified 6 forfeiture events which, if any occurred, would have the FDA deny a first-filer ANDA its 180 days of market exclusivity.

These six events are, in short:
(1) Failure to Market: if the first applicant fails to market its product under a variety of circumstances and time frames. (2) Withdrawal of Application: If the first applicant withdraws its application or it is deemed to have been incomplete. (3) Amendment of Certification: if the first applicant amends or withdraws its patent certifications.
(4) Failure to Obtain Tentative Approval: if the first applicant fails to obtain tentative approval for its ANDA within 30 months after it was filed.
(5) Agreement: if the first applicant enters into an agreement that violates antitrust law.
(6) Expiration of Patents: if the relevant patents expire.

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Sources
FAQ on Patents and Exclusivities Frequently Asked Questions on Patents and Exclusivity | FDA

Transcript http://www.fda.gov/Drugs/ResourcesForYou/HealthProfessionals/ucm315519.htm

Para IV Forfeitures http://www.paragraphfour.com/explained/basics.htm

Market Realist - Excellent Long read Is a Para IV Filing Rewarding for a Generic Company?

Commentary on Forfeiture due to 30 month lapse FDA Petitioned on 180-Day Exclusivity Forfeiture for Tentative Approvals that Occur on the 30-Month ANDA Submission Anniversary Date

Reuters PPT -
First to File and Beyond: Paragraph IV Business Strategies http://thomsonreuters.com/content/dam/openweb/documents/pdf/pharma-life-sciences/misc/burck-paragraph-iv-webinar.pdf

USFDA - GpHA Quarterly GDUFA Review with Detailed explanation of Hatch‐Waxman Amendments http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM442070.pdf

Request feedback from @ankitgupta and @ananth.

[ananth]

@crazymama Great digging.

What I have figured out is that, once the innovator files the NDA for NCE, after four years(NCE-1) generics can apply for para iv. After that, the stay for 30 months stays, which basically means ftf/shared ftf will only come after 6.5/7 years after the launch by the innovator.
The innovators will have free run for 6-7 years with out any competition or pricing pressure.
In india, there are no innovators (but many are trying to get there like SPARC), but there are suppliers to these innovators like CRAMS (contract research and manufacturers) service providers.
Innovators typically take from 2-3 suppliers and the relationship is quite sticky in nature and has much higher margins.

So, whoever filed the para IV first after four years, get the FTF for 6 months. There can multiple players too, in that case FTF will be shared.

On tentative approval of generics, yes you are right that TA does not necessarily mean final approval. we have seen in abilify cases where TA did not convert to final approval. Basically, I take it as a indication that generic company has filed for that molecule.
For example: in the case of Torrent, since they do not do much API, it is difficult to know the pipeline. But, they have got tentative approval for Benicar some time back. So, it gives some indication.

Yes, for dates, even I look at mostly the exclusivity expiration dates on fda site as well as other websites/research reports.

I will read up the links you have put up and get back.

[madhug]

FDA Warns Sandoz, Dr. Reddy’s Indian Sites Over Data Integrity Violations

[ankitgupta]

Hi Vishnu,

Great effort! It personally enhanced my knowledge of lot of fronts especially on tentative approvals. From what has been mentioned in the reports, it now becomes clear that Cadila and Sun didnt get final approval for gAbilify on account of 483 issues at their plants.

I think one thing is clear that most of the big and medium sized companies are eyeing the FTF filings and it will mostly be shared FTFs in many of the big molecules that are expiring in the medium to long term until and unless its a complex molecule or has different delivery system like injectables, drops etc as not many companies have that ability. Also, its still becomes difficult for us as analysts to identify whether the company has filed ANDA for a particular molecule or not in case the company is not backward integrated into APIs. We will have to rely on litigation search that we can do on google or rely on research reports.

Also, its still not clear for us to exactly estimate the time of approval of generics until and unless its a big blockbuster molecule like gAbilify or may be gCrestor because few companies had tentative approvals for it and the innovators were trying to extend the patent beyond a certain date. I will just give you an example here. Alembic seems to have filed an ANDA (its there in their DMF file) for gTraceleer (Bosentan) whose exclusivity has expired but patent expired only on November 20, 2015. I was expecting some of the generic companies to get approval for this ANDA post November 20, 2015 but none have got till date. Its still a pretty big molecule with market size of more than a billion dollar in US. Another example I can give you is of gNexium. As per concalls, it seems that Lupin has also filed for its ANDA but hasnt got approval till date. Seems some issue with filing and Bioequivalence studies etc. Here if the launch of the molecule gets delayed and other companies come in it becomes difficult for a new entrant to garner market share and milk the molecule as it would have done if it was amongst the first to launch. We can establish the molecule pipeline for the companies easily in case of backward integrated ones like Alembic but to accurately estimate when the ANDA approval for the molecule is expected is still a big challenge. Companies like Torrent have their own challenge of identifying the drug pipeline itself.

I think there are lot of issues that we need to understand and still cannot be 100% sure what will happen!

[rk21]

Could someone enlighten me on the current status of the ban on Glenmark infringement via ZITA 100(Sitagliptin). This might seriously affect the results of the company. Obliged -rk21

[crazymama]

FDA Overhauls Inspection Operations

SourceURL:

FDA Overhauls Inspection Operations

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Below is a snapshot of important points.
Recommend to read the above link for more details.

This article gives us a better insight into the recent upsurge in warning letters or import alerts from FDA. IMHO their IT Platform “Panorama” has been stabilized alongwith the trend of longer period of inpsections of 1-2 weeks as against 3 days pre-GDUFA would indicate this trend is likely to continue.

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Transforming ORA
The reorganization of FDA’s 5000-person field force represents the most important change since the Office of Regulatory Affairs (ORA) was formed, says Melinda Plaisier, ORA chief and associate commissioner for regulatory affairs. This Program Alignment initiative, announced in September 2013 and further clarified in February 2015 (1), is dissolving ORA’s five regional offices and establishing commodity-based and vertically integrated inspection programs for drugs, biologics, medical devices, tobacco products, food, and bioresearch monitoring that will operate out of ORA’s 20 district offices.
…
These teams of specialized investigators will gain greater technical expertise through training, which should help them keep pace with manufacturing changes and new technology, especially those inspectors with sub-specialties in, for example, sterile drugs, compounding, APIs, or combination products. Pharmaceutical inspectorate members also will be part of the Center for Drug Evaluation and Research (CDER) product review teams so that they will fully understand development and manufacturing issues involved in a new therapy and can produce pre-approval inspection reports that reflect a common understanding of pertinent production and quality concerns.

Plaisier emphasized that the ORA overhaul is a “work in progress,” and that many final decisions and individual assignments are still to come. Questions remain about the number of field management teams for each program, where these will be located, and how to align some 2000 investigators into the different review programs, she explained. These transition activities will continue through the coming year, with the goal of starting up the new model in fiscal year 2017. ORA is looking to develop metrics to measure the impact of these changes internally, along with enhanced training programs, new work planning systems, and more centralized laboratory operations.

Coordinating compliance
…
These changes should accelerate re-reviews of plants looking to regain compliance status and “not leave firms in OAI (official action indicated) status for a long time,” Cosgrove commented at the PDA/FDA conference. He emphasized the importance of complete documentation of operations to demonstrate compliance with GMPs.** He also noted that documentation by itself “is not enough” to demonstrate full compliance and that FDA inspectors are being trained to do a “deeper dive” into actual production practices.**

FDA also seeks to halt violative imports more quickly by de-linking import alerts from warning letters. Expeditious action against noncompliant imports is important, Cosgrove pointed out, because many of these products raise data integrity issues, including data that have been deleted, back-dated, copied, and fabricated. FDA is highlighting data-integrity failures because such problems also are linked to GMP violations and other problems that represent “real risk to patients.”

OMQ also is looking hard at contract manufacturers and how well their pharma clients monitor contract operations for quality and compliance. Clients need “to get out there,” perhaps put a person in the plant, to uncover GMP and compliance problems “before we do,” Cosgrove advised. He noted that the manufacturer holding the approved license for a medical product is responsible for ensuring quality at all its production facilities—including those overseas or operated by partners and suppliers.

Amidst all these organizational changes, FDA is developing a new model for assessing plant operations based on standardized measures of a facility’s state of quality and compliance. The New Inspection Protocol Project (NIPP) will apply to pre-approval, GMP surveillance, and for-cause inspections. CDER’s Office of Pharmaceutical Quality is developing the new protocols and planning pilot NIPP inspections with ORA. The aim is to obtain quantitative scores that can help compare sites, while also reducing variability in observations by different inspectors and providing manufacturers with a clearer idea of what they need to do to maintain quality. While continuing to document observed deficiencies, inspections also will identify practices that exceed basic compliance requirements to reward positive behaviors.

Global collaboration
…
FDA conducts thousands of foreign inspections each year, many in Europe, Corrigan pointed out, and reliable information indicating that a facility meets GMPs and is a low-risk operation could help avoid unnecessary site visits.** To move forward with a mutual reliance initiative,** FDA investigators are observing audits of EU inspectorates, which are conducted by other EU member states as part of their own internal mutual reliance inspection program. At the same time, EU officials are auditing ORA district operations to support increased EU reliance on FDA inspection practices and reports.

Corrigan noted that FDA officials have been impressed with the high level of discussion taking place during these audits, but a number of important issues have to be addressed for the initiative to move forward.
…
This is a high priority for both FDA and the EU, and, Corrigan stressed, “we want to succeed.”

[csteja]

@ananth, @crazymama

If a generic company wrongly challenges innovator after 4 yrs (say) and got banned for 30 months , will it still hold the FTF advantage after 30 months (at end of 6/7 years when patents get expired) ?

If so, what is stopping all the generic companies to file first ?

Will the generic companies be fined for losing patent challenge ?

Suppose a generic company won the patent challenge in court. It signifies that the generic company is making the medicine/API with different molecule than the innovator. In such a case, can the generic company apply for patent (for 6-10 years) on the API.

I am very new to pharma concepts. Please forgive if my understanding or terminology is poor.

[crazymama]

Hello Teja,

You have misunderstood couple of things. So i will first explain the facts and then answer ur queries.

First off the Generic version has to be the same molecule/API. If it were a different molecule then it wouldn’t be a generic in the first place.

So, a Para IV litigation is typically premised on the rationale that the Generic has not infringed the original patents as they are making the API through a different process(which is backed by their own patent - one of the reasons why @ananth asked to include patent info in the original template)

FDA wants and encourages Generic companies to file Para-IV ANDA’s and undertake the hassle of fighting the litigation in courts. The reward for this is the 180-day exclusivity period wherein they can easily recoup their litigation costs and some.

30-month stay period is not a ban but a fine-balancing act to protect the innovator on one side while trying to minimize drug costs by encouraging generics to file and market before patent expiry. This applies to the FDA and forbids them to provide final approval until the litigation has been settled.

To minimize the impact of the 30-month stay period -

@crazymama

– ANDAs with Paragraph IV certification may be submitted four years after regulatory approval (NCE -1), but may not receive approval until the expiration of the exclusivity period

Hope your queries have been answered.
Please read the earlier posts in the thread, as most of ur queries are covered there.