INTRODUCTION: ^1,2,3

The sponsor or manufacturer for requesting permission to submit an ANDA for a generic drug product that differs from the RLD in Route of Administration, Dosage form or strength or the different active ingredients in a fixed combination drug product submits suitability Petition to the FDA.

Criteria for not considering the suitability petition:

· Safety and Effectiveness of the change proposed by the sponsor comparing to the RLD cannot be evaluated without conducting any investigations that may be not submitted under ANDA.

· The change requested cannot follow the pathway of ANDA approval and submit the New Drug Application.

· The requested change needs the Pediatric studies but no pediatric study waiver is given. As Pediatric research equity act the safety and efficacy studies on the pediatric has to be done.

Approval procedure:

· Suitability petition submitted to dockets of management is forwarded to project manager in the division of legal and regulatory support

· In next step from division of legal and regulatory support, the suitability petition is transferred to the division of filing review.

· The primary reviewer does the following work:

i. A summary is written about the submitted suitability petition which contains following information:

a. Content and Format of the suitability petition should comply with the 21 CFR 10.30, RLD related information is taken from orange book and copies of the RLD and proposed labeling and any information related to the pediatric research equity act waiver request information is checked.

b. Identifies whether any other such petition, which resembles it, is filed to the FDA.

c. Identifies whether FDA already approves the drug mentioned in the suitability petition for change.

d. Identifies if any additional information is needed and the all information is forwarded to project manager of DFR to communicate with petitioner and get response

· Generates a clearance sheet

· Identifies whether the scientific experts present in office of generics or scientific experts from the outside of the office of generics evaluate submitted suitability petition.

i. Primary reviewer prepares the consult request.

ii. The consultant request is forwarded to the DFR secondary reviewer and the DFR PM

· Written summary is forwarded to the DFR secondary reviewer.

· DFR secondary reviewer reviews the summary and consultant request prepared and forwarded by the DFR primary reviewer.

· DFR secondary reviewer prepares a consult package and forwards to the DFR project manager for distribution.

· The DFR project manager does the following:

i. Consult requests are sent by the DFR project manager which are prepared and received from the DFR primary reviewer.

ii. The Consult responses are received from the consult experts.

iii. If any additional information is needed from the petitioner which is determined by the DFR primary reviewer. The DFR project manager does the additional information request.

iv. The consult request to another division is asked. Division of clinical review consult request is asked if the opinion of the DFR and consulting officer differs for the proposed change in suitability petition.

· DFR Project manager receives the consult request from the DFR primary reviewer and DFR project manager forwards it to the division of clinical review for reviewing it

· The medical officers and other secondary reviewers review the suitability petition.

· After receiving the consult request from the DFR project manager, the DFR review team does the following:

i. It reviews the complete suitability petition and responses obtained from the consultancy and any other information related to clinical data, which are related to petition.

ii. Final decision related to approving or denying of the suitability petition is discussed.

A. If the division of clinical review team do not agree with the recommendations given by the experts of the office of generics or outsourced experts, then the medical officer contacts the experts and resolves the issues.

B. If the medical officer determines that the extra experts are needed for reviewing, the request is forwarded to DFR project manager.

C. Issue is resolved by discussing with additional experts.

D. After the additional review by the new experts, their recommendations are taken and evaluated.

E. Final decision is given to approve or deny the petition

· After the DCR review, team recommendations the DFR primary reviewer collects all the responses and prepares a draft response sheet for the suitability petition submitted.

· The draft response suitability petition package is forwarded to the DLRS primary policy reviewer.

· The DLRS primary policy reviewer:

I. They review the comments submitted in public docket related to suitability petition. It determines any adverse comments are present public docket.

II. It identifies the listed drug submitted for change is approved in orange book or not.

III. It identifies whether the RLD mentioned in the suitability petition is withdrawn or discontinued due to the safety and efficacy issues. All related issues are determined.

IV. If the suitability petition is containing any novel information and suitability petition is to be denied then, a consult request is sent to FDA’s office of chief counsel

V. The draft response prepared is revised and new responses from the consult are included and informs the OGD deputy director. The Deputy Director should sign the following suitability petition.

VI. The final suitability petition response package is forwarded to DLRS secondary policy reviewer for reviewing.

· The DLRS secondary receives the suitability petition response package, reviews the all responses, and forwards to the ODG deputy director for the signature and clearance of the form.

· The OGD deputy director finally reviews the suitability petition response package and gives clearance for the final package by signing the response petition.

· The signed copy is sent back to DLRS secondary policy reviewer

· The DLRS secondary policy reviewer forwards the signed copy of suitability petition response to the DLRS project manager.

· DLRS project manager fortify the signed copy of Suitability petition is mailed to the petitioner.

· The other copy is sent to dockets of management staff to add the suitability petition in docket.

Content and Format of Suitability Petition:

Any suitability petition submitted to FDA should comply with 21 CFR 10.20 format. If the suitability petition is not complying with 21 CFR part 10, FDA does not accept the suitability Petition that is submitted. It should contain following contents:

A. Action Requested

B. Statement of grounds

C. Environmental Impact

D. Economic Impact

E. Certification

Effective date should be included at the top of the Petition and followed by address of the Division of Dockets of management.

In Next Paragraph, the information related to under which sections and act they had applied to take the action requested.

A. Action Requested:

In this section, the Petitioner should clearly explain about the action to be taken by the FDA. The action requested may be to amend the regulation (may be an amendment) or order.

Petitioner may also request to FDA to refrain any order issued by the FDA.

B. Statement of Grounds:

In this section, the Petitioner explains in detail about the action to be taken. Petitioner should give all the information related to the legal backgrounds of the action requested. Starting from the approval of product all the information should be included. The all applicable Information and outlook on which the aspects the petitioner depends should be clearly explained. All aspects of information, which is known to the Petitioners knowledge, should be included.

C. Environmental Impact:

If any Environmental Impact is present related to action requested, the following statement should be provided. Environmental assessment information should be given.

D. Economic Impact:

In this section, information is submitted only when the FDA commissioner of Dockets of Management requests the Petitioner. The following section information is submitted only when it is related to:

i. Cost or Price increased and impacts the government & consumers

ii. Work rate & yield of wage earners, Businesses & government

iii. Competition

iv. Supplies related to important materials and products or services

v. Employment

vi. Energy supply or demand.

E. Certification:

At the end of the petition, it should contain an undersigned certificate given by the petitioner mentioning that, the above-submitted information is known to his best knowledge and the all the above information provided contains all the views of the Petitioner.

At end the Name and Signature of Petitioner, including the Mailing address & Telephonic number should be included.

Case Studies:

Petition summary: 1⁴

Petition docket number: FDA-2013-P-1202,

Petitioner: Olsson Frank Weeda Terman Matz PC,

Product name: Vancomycin Hydrochloride For Injection, USP, Fliptop Vial For Intravenous Use,

Petition submission date: 27/09/2013

Petition responded date: 06/01/2017

Petition summary submitted by Olsson Frank Weeda Terman Matz PC:

Petitioner requested the FDA that Vancomycin Hydrochloride For Injection USP, 1.5grams (base)/vial can be submitted as the ANDA. RLD approved by the FDA manufactures by Hospira is Vancomycin Hydrochloride for Injection, USP, and Fliptop Vial for Intravenous Use, 1 gram (base) / vial. It is approved under application number A62912. The Petitioner manufactures the Vancomycin Hydrochloride for Injection, USP relays on the RLD of Hospira for submission of ANDA. The ANDA submitted by the manufacturer should have same strength, dose, concentration, same amount of inactive ingredients, and same route of administration. However, here the Olsson Frank Weeda Terman Matz PC wants to change the strength of the dosage form from 1gram (base)/vial to 1.5 gram (base)/vial.

Previously Hospira has submitted a supplement for 750mg (base)/vial before it was submitted as the suitability petition Docket No. 2006P-0533/CP1. FDA has granted permission to file the ANDA, which varies with RLD in strength from 1gram (base)/vial to 750mg (base)/vial. The same related petition has been submitted by the Olsson Frank Weeda Terman Matz PC seeking permission for change in strength in comparing to RLD remaining all are similar. The Draft labeling of the change proposed for the Vancomycin Hydrochloride for Injection USP, 1.5grams (base)/vial is submitted. In the labelling, it is mentioned that 15mg/kg is the minimum dose used to treat the mild and moderate renal impairment patients and anephric patients. The 1.5grams (base)/vial is sufficient for the patients who weight b/w 67-100kg. If it is 1gram (base)/vial, the physician or any clinician uses two different vials and to get dose of 15mg/kg.

For the proposed strength, there is no safety and efficacy issues, as they do not differ from RLD in any aspect except the strength.

Petition response by FDA:

The FDA responded to the petition submitted by Olsson Frank Weeda Terman Matz PC that, it will approve the change in the strength which varies from the RLD. Because FDA concluded that there no safety and efficacy issues to the proposed strength. As the proposed strength, studies are listed in the RLD labelling the FDA accepted for the change.

The petitioner has to conduct the required bioequivalence studies and prove that the proposed strength is therapeutically equivalent to the RLD. If FDA is approving, the petition does not mention that ANDA is approved. If the ANDA meets all the requirements related to the FDA during the review of the documents submitted by the petitioner.

The petitioner for getting approval for ANDA has to submit the additional data required by the FDA. Petitioner has to rely on the RLD, which has been mentioned in the petition. The Approved letter by the dockets of management, docket number and information related to petition should be submitted along with ANDA.

Decision by FDA: Granted.

Petition summary: 2⁵

Petition docket number: FDA-2014-P-0142,

Petitioner: Emcure Pharmaceuticals USA Inc.,

Product name: Pantoprazole Sodium for Injection (40mg/vial) USP,

Petition submission date: 23/01/2014

Petition responded date: 28/11/2016

Petition summary submitted by Emcure Pharmaceuticals USA Inc.:

Wyeth Pharmaceuticals Inc. first got approval for the Pantoprazole Sodium for Injection USP and manufactured with proprietary name Protonix^®.it was approved on March 22,2001 under the application number N020988. Protonix^®is supplied as Freeze-dried powder packed in a glass vial and closed with rubber stopper and crimp seal outside. Each vial contains Pantoprazole sodium, which is equivalent to 40mg of Pantoprazole. The vial has to be reconstituted with 10mL of 0.9% NaCl and dilute it with 100mL of the any one of three commercially available diluents (5% Dextrose injection USP, 0.9% sodium chloride, Lactated Ringer’s solution) to obtain the final concentration of the 0.4mg/ml and it should be administrated using the In-Line filter which is supplied along with Protonix^®. Its storage condition is b/w 2^oC – 8^oC. Protected from the light.

Wyeth Pharmaceuticals Inc. submitted the supplement for the FDA, which is reformulated.

The revised formulation contains the 40mg of Pantoprazole sodium, 1mg of edetate disodium and Sodium hydroxide used as the buffer for adjusting the pH. Protonix^®revised formulation is supplied as Freeze-dried powder packed in a glass vial and closed with rubber stopper and crimp seal outside. The vial has to be reconstituted with 10mL of 0.9% NaCl and dilute it with 100mL of the any one of three commercially available diluents (5% Dextrose injection USP, 0.9% sodium chloride, Lactated Ringer’s solution) to obtain the final concentration of the 0.4mg/ml. In the revised formulation, there is no need of using the In-Line filter. Its storage condition is b/w 2^oC – 8^oC. Protected from the light.

Wyeth Pharmaceuticals Inc. submitted another supplement for the FDA, which is reformulation of Protonix^®. The revised formulation contains the 40mg of Pantoprazole sodium, 1mg of edetate disodium and Sodium hydroxide used as the buffer for adjusting the pH. Protonix^®revised formulation is supplied as Freeze-dried powder packed in a glass vial and closed with rubber stopper and crimp seal outside. The vial has to be reconstituted with 10mL of 0.9% NaCl and dilute it with 100mL of the any one of three commercially available diluents (5% Dextrose injection USP, 0.9% sodium chloride, Lactated Ringer’s solution) to obtain the final concentration of the 0.4mg/ml, 0.8mg/ml and 4mg/ml. In the revised formulation the storage condition is b/w 2^oC–8^oC was removed and can be stored at room temperature. Protection from the light is also not applicable. The use of In-line filter was removed completely.

The Petitioner Emcure Pharmaceuticals USA Inc. requests the FDA the ANDA can be submitted relying on the discontinued product, if it is not discontinued based on the safety and efficacy issues. Petitioner mentions that Protonix^®original formulation did not mention anywhere that it is revised based on safety and efficacy issue. However, the Wyeth Pharmaceuticals Inc. gave a statement that Protonix^®original formulation is used for about 7yrs by the 5 Million people with the In-Line Filter. The Successive reformulations of Protonix^®made the storage easy and can be used without filters.

The Change proposed by the Emcure Pharmaceuticals USA Inc. is that they are relying on the Protonix^®original formulation but the temperature conditions maintained are b/w 20^oC–25^oC and the excursions allowed are b/w 15^oC-30^oC. It can be administered with using In-Line filter. It is supplied as Freeze-dried powder packed in a glass vial and closed with rubber stopper and crimp seal outside. Each vial contains Pantoprazole sodium, which is equivalent to 40mg of Pantoprazole.

Rationale explained by the petitioner that, when the Protonix^®is reconstituted with 10mL of 0.9% NaCl and dilute it with 100mL of the any one of three commercially available diluents (5% Dextrose injection USP, 0.9% sodium chloride, Lactated Ringer’s solution) to obtain the final concentration of the 0.4mg/ml there is formation of particulates in the I.V solution. So it should be administered with In-line filters. According to the USP chapter 36, the particulate count in the vial should be within limits mentioned. For Small volume, parenteral if the particle size is ≥10 µm then the NMT 6000 particles should be present. if the particle size is ≥25 µm then the NMT 600 particles should be present. The no. of particles present in the glass vial is analyzed by the Light obstruction particulate count test.

Petitioner clearly mentions that proposed formulation complies with the USP chapter 36. The Storage conditions-maintained b/w 20^oC–25^oC and the excursions allowed are b/w 15^oC-30^oC. The Petitioner also committed that if it is compulsory to provide In-Line filter along with the drug product as per FDA instructions it was ready to implement that.

Petitioner requested FDA to determine that Protonix^®original formulation is not discontinued based on the Safety and Efficacy issue and requested for the waiver for not using the In-Line filter with proposed change or formulation.

Petition response by FDA:

FDA has denied the petition of the Emcure Pharmaceuticals USA Inc. based on the following reasons; Protonix^®original formulation was discontinued based on the safety and efficacy reasons. The reconstituted solution is administered through IV via using the In-line Filter because after reconstitution the solution contains the particulates. In the post marketing there are many adverse events reported. The ADRs are due to the improper use of the In-line Filter and some Protonix^®original formulation is administered directly through IV without any In-line Filter.

The FDA has taken three commitments from the Wyeth that it should reformulate the drug product within 2yrs by eliminating the In-Line filter use and Co-Packaging has to be updated. After 3yrs, the formulation was revised containing the Edetate Disodium and Sodium hydroxide, which reduced the particulate count formation. In 2004, again the formulation storage conditions were changed to the room temperature.

FDA refused for the approval of proposed change by the Petitioner as the inactive ingredients used by the Wyeth reducing the particulate formulation and reduced the use of In-line filters and made easy for administration. At first, it was approved based on the unmet needs of patients. FDA did not grant the petition for the change proposed as the Protonix^®original formulation is discontinued based on the safety and efficacy reasons.

Decision by FDA: Denied.

A Short survey regarding suitability petition is submitted in the following pages:⁶

Statistical reports of Suitability petitions

Table:1- ANDA Suitability Petitions received b/w 2007-2018

Year	Total no. of Pending Petitions	Total no. of Responded Petitions	Total no. of Withdrawn petitions	Total no. of petitions submitted
2018	103	59	7	169
2017	45	75	17	137
2016	26	94	17	137
2015	32	65	12	109
2014	34	89	15	138
2013	25	70	11	106
2012	12	56	21	89
2011	7	41	23	71
2010	11	55	16	82
2009	19	40	14	73
2008	16	39	10	65
2007	20	23	131	174

Graphical Representation of the Suitability Petitions filed:

Figure-1: No. of Suitability petitions filed

Issues and Concerns:^{7, 8, 9}

Pending Suitability Petitions:

FDA is not responding to the petitions submitted by the manufacturers according to the goal dates. The no. of responded petitions is very few. There are some petitions, which are pending since many years. Some petitions related to the ANDA suitability is not updated since 2015. Cases of suitability petition available, which were not yet answered and required to answer, based on safety focus.

Timeline:

The timeline proposed by the FDA for Suitability petition is 90 days. However, the many petitions are not receiving the response within the timeframe mentioned by the FDA. The FDA has many pending suitability petitions since 2014. Many generic manufacturers are waiting for the response given by the FDA.

Monopoly:

The FDA does not respond ANDA suitability petitions are submitted by the generic manufacturers. Which indirectly gives benefit to the Innovator that no generic can enter into market. The Innovator is the only person present in market and financially benefited.

Drug Price:

Until the generic manufactures enter into the market; the drug price will be very high. The Innovators submit a petition regarding the stay of the approval for the pending ANDA or NDA. The stay for the Pending ANDA and NDA is given. The reasons generally mentioned by the innovators are not scientifically valid, to just give stay for the approval of pending ANDA and NDA, it submits a petition.

CONCLUSION:

The above trending data indicates that the no. of Petitions submitted every year has been increased. The review goal dates are not achieved as per mentioned in the FDA Guidance’s “Citizen Petitions and Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act Guidance for Industry” and “ANDA Suitability Petitions.”

Considering above reason the following change is proposed:

Online Tracking System:

· FDA has implemented CDER Direct NEXTGen Collaboration Portal for submission of the CC.

· CC can be submitted through online portal of FDA.

· After submitting CC with required information, the CC can be tracked until the Sponsor receives the response from FDA

· In similar way, the FDA can implement an online tracker for checking the status of the submitted petition. If the FDA takes more than 150 days- Citizen Petition or 90 days-ANDA suitability Petition (maximum responding time given by FDA) to respond, it should notify the petitioner the reason for delay and time taking for responding to the petition.

Review by Country Specific:

· Review Procedure for FDA can be changed. The following changes can be done: Nationalized review procedure can be implemented.

· FDA can implement the change in reviewing procedure: Citizen of particular country can submit the petition to FDA organization in that country.

· Therefore, the time of reviewing will be reduced and Increased Pending Petitions can be eliminated.

REFERENCES:

1. [Internet]. Fda.gov. 2018 [cited 24 October 2018]. Available from: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm583436.pdf

2. [Internet]. Fda.gov. 2018 [cited 24 October 2018]. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM622235.pdf

3. [Internet]. Fda.gov. 2018 [cited 24 October 2018]. Available from: https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProcedures/UCM365676.pdf

4. Regulations.gov [Internet]. Regulations.gov. 2019 [cited 11 March 2019]. Available from: https://www.regulations.gov/document? D=FDA-2014-P-0142-0004

5. Regulations.gov [Internet]. Regulations.gov. 2019 [cited 11 March 2019]. Available from: https://www.regulations.gov/document?D= FDA-2013-P-1202

6. [Internet]. Fdalawblog.net. 2019 [cited 11 March 2019]. Available from: http://www.fdalawblog.net/wp-content/uploads/CPTracker. xls

7. Vokinger K, Kesselheim A, Avorn J, Sarpatwari A. Strategies That Delay Market Entry of Generic Drugs. JAMA Internal Medicine. 2017;177(11):1665.

8. Chen B, Yang Y, Cheng X, Bian J, Bennett C. Petitioning the FDA to Improve Pharmaceutical, Device and Public Health Safety by Ordinary Citizens: A Descriptive Analysis. PLOS ONE. 2016;11(5): e0155259.

9. Drug Companies Filing Citizen Petitions. Biotechnology Law Report. 2012;31(6):592

Received on 11.10.2019 Modified on 18.11.2019

Research J. Pharm. and Tech. 2019; 12(12): 5985-5990.

DOI: 10.5958/0974-360X.2019.01039.4

Criteria for not considering the suitability petition:

Approval procedure:

Content and Format of Suitability Petition:

A. Action Requested:

B. Statement of Grounds:

C. Environmental Impact:

D. Economic Impact:

E. Certification:

Case Studies:

Petition summary: 14

Petition summary submitted by Olsson Frank Weeda Terman Matz PC:

Petition response by FDA:

Petition summary: 25

Petition summary submitted by Emcure Pharmaceuticals USA Inc.:

Petition response by FDA:

Petition summary: 1⁴

Petition summary: 2⁵