Sun Pharma told to submit revised CT protocol for Ferric Pyrophosphate Citrate Solution

New Delhi: In response to the drug-major Sun Pharma Ltd's phase 3 protocol of Ferric Pyrophosphate Citrate Solution, the Subject Expert Committee (SEC) functional under the Central Drugs Standard Control Organization (CDSCO) has opined the firm to revise the protocol and submit the revised clinical trial protocol to CDSCO for further review.

This came after the firm presented the Phase III clinical trial protocol for Ferric Pyrophosphate Citrate Solution, 27.2 mg Fe/5 mL) before the committee, as per the earlier recommendation of the SEC dated 25.07.2020 & the technical committee recommendation dated 26.04.2021.

Ferric pyrophosphate citrate is a soluble iron compound used to maintain haemoglobin levels in patients undergoing hemodialysis.

The usage of ferric pyrophosphate is based on the strong complex formation between these two species. Besides, the capacity of pyrophosphate to trigger iron removal from transferrin, enhance iron transfer from transferrin to ferritin and promote iron exchange between transferrin molecules. These properties make it a very suitable compound for parenteral administration, iron delivery into circulation and incorporation into hemoglobin.

Previously, during SEC meeting in 2017, the company applied for permission to import and market a new drug product, Ferric Pyrophosphate Citrate solution, for parenteral administration with bicarbonate concentrations of 27.2 mg Fe/5 ml and 272 mg Fe/5Oml, which is indicated for the replacement of iron in adult patients with hemodialysis-dependent chronic kidney disease (HDO-CKD).

The firm also submitted the application with a request for a waiver of the country's local clinical trial regulations at the same meeting.

In response, the committee stated that there are alternatives in the country for the suggested indication. As a result, the committee suggested that the firm perform a local Phase Ill clinical trial in the country, and that the protocol and other documents be submitted to the DCG (I) office for review.

In continuation, last year the company again presented justification for a clinical trial waiver for Ferric Pyrophosphate Citrate Solution at an SEC conference .

However, following extensive review, the committee repeated its recommendation, stating that there are available alternatives for the suggested indication, and that the firm should perform a local Phase Ill clinical trial and submit the protocol and other documents for assessment.

After that, in line with the firm's request, the matter was sent to the Technical Committee, where Sun Pharma, a leading pharmaceutical company, requested a waiver to conduct a local Phase III clinical study, citing the following arguments:

• Ferric Pyrophosphate Citrate Solution, 27.2 mg Fe/ 5 ml is the only iron product that is US FDA approved for delivery via dialysate indicated for the replacement of iron to maintain haemoglobin in adult patients with HDD-CKD.

• Ferric Pyrophosphate Citrate Solution of Rockwell Medical is approved by US FDA on 23rd January 2015 and is commercially launched in USA in September 2015.

• There are no unexpected serious adverse events reported with Ferric Pyrophosphate Citrate Solution in USA since its launch.

• Ferric pyrophosphate citrate is the first iron salt devoid of carbohydrate to be considered for parenteral administration in over 100 years.

• No approved IV iron product has an indication for a continuous maintenance regimen in haemodialysis-dependent chronic kidney disease patients in India. Therefore, there is an unmet need in haemodialysis-dependent chronic kidney disease patients.

• Ferric Pyrophosphate Citrate Solution is indicated ONLY for Haemodialysis-dependent chronic kidney disease patients which is rare disease/condition in India.

• There is an unmet need for Ferric Pyrophosphate Citrate Solution in India as currently there is no available therapy which is indicated for the maintenance of Haemoglobin in haemodialysis-dependent chronic kidney disease patients.

• CL:Jrrently used intravenous iron agents, iron sucrose and iron carboxymaltose, are used on a weekly-monthly schedule even though efficacy and safety of these agents have never been demonstrated in long term studies .

• The safety and efficacy of Ferric Pyrophosphate Citrate Solution in patients with HDD-CKD was assessed in two randomized, single blind, placebo-controlled clinical trials (SFP-4-RC and SFP-5-RC) . Study was conducted in 305 patients and 294 patients in SFP-4-RC and SFP-5-RC respectively.

• There were no deaths or events of suspected hypersensitivity reactions due to Ferric Pyrophosphate Citrate Solution in these studies .

• A number of clinical studies (including phase I, II and Ill) have been conducted to evaluate the safety and effectiveness of Ferric Pyrophosphate Citrate Solution (27.2 mg Fe/5 ml) in USA and Canada on different race categories including Caucasians, African Americans, Hispanics and some Asians and American Indians.

• The clinical trials performed on Ferric Pyrophosphate Citrate Solution fulfils the ICH requirements (ICH Guideline ES (R 1) On 'Ethnic Factors in the Acceptability of Foreign Clinical Data') of extrapolating the clinical data to the new region (in this case, India).

• Ferric Pyrophosphate Citrate is insensitive to ethnic factors and that the clinical studies that were concluded in the American population in the USA are valid for Indians.

• As of 31 December 2019, there were 40,200 patient days of exposure (110 patient-years of exposure) to Triferic ampules. There has been a total of 1,442,000 patient days for all dialysate Triferic based on based on commercial sales distribution .

• Chronic Kidney Disease is classified as Rare Disease in India as per Organization for Rare Disease India (ORDI). Haemodialysis therapy is much more rare than Peritoneal dialysis.

• As per an Office Memorandum dated 1st February 2019 issued by Ministry of Health and Family Welfare, Haemodialysis is considered as a Rare Disease in India.

• As per published article in 2018, India is expected to have 1,20,000 patients on Haemodialysis and as per New Drug Clinical Trial Rules 2019, Orphan drug means a drug intended to treat a condition which affects fewer than two lac person in India. From the above factor we can deduce that Ferric Pyrophosphate Citrate solution can be an orphan drug in India.

• As per Rule 75 (7) of New Drugs and Clinical Trials Rules, 2019, if the new drug is approved and marketed in other countries internationa lly, the local clinical trial may not be required.

• In the past, based on recommendation of Technical Committee in its 44th meeting held on 05th September 2018 recommended for CT waiver and accordingly drug product Sucroferric Oxyhydroxide bulk & Sucroferric Oxyhydroxide Chewable tablets 500 mg for the control of serum phosphorous levels in patients with chronic kidney disease on dialysis was approved in India on 18.04.2020 with a local clinical trial waiver.

"In lieu of all above, as the drug product is internationally available in well-regulated country like USA, number of well-controlled studies conducted with the drug and it fulfills the criteria of non-sensitivity to ethnical factor, we strongly believe that the internationally conducted clinical studies can be considered as valid for Indian population. Also the drug fulfills the criteria of local clinical trial waiver as per New Drugs and Clinical Trials Rules, 2019. Hence, we seek wavier from conducting local clinical trial", the company added.

After considering all of the arguments, the technical committee agreed with the SEC's recommendations and advised that the firm perform a local Phase Ill clinical study and submit the protocol and other documents to the SEC for evaluation.

Further, at the recent 91st SEC meeting for Cardiovascular and Renal, an expert panel assessed the Phase III clinical trial protocol for Sun Pharma's Ferric Pyrophosphate Citrate Solution, 27.2 mg Fe/5 ml).

After detailed deliberation, the committee opined that

1. The range for the upper limit of serum ferritin and TSAT for giving Ferric Pyrophosphate Citrate in the treatment arm should be included in the inclusion criteria.

2. Test for Folic acid and Vitamin B12 deficiency need to be performed before inclusion of patients in the study.

3. Hepatitis B, Hepatitis C, Occult TB and latent TB test should be performed for exclusion of patients from the study and Lab investigations and documents shall be maintained .

5. Primary End points should be Hb and iron markers (TSAT, Ferritin, TIBC etc.) rather than IV iron as rescue therapy.

6. During the conduct of the trial, during Phase-II of the study, change in ESA, blood transfusion and use of any form of iron should be clearly defined.

Accordingly, the expert panel directed the firm to submit a revised clinical trial protocol to CDSCO for further review by the committee.