IND Minutes held on 06.08.2015 - Central Drugs Standard Control

Minutes of IND Committee meeting held on
06.08.2015 at 11:00 AM in CDSCO (HQ),
FDA Bhawan, Kotla Road, New Delhi – 110 002
List of Participants:
1. Dr. Y.K. Gupta, Prof. & Head, Deptt. of Pharmacology, AIIMS, New Delhi.
2. Dr. A.K. Saxena, Scientist-G, Central Drug Research Institute, Lucknow.
3. Dr. Nilima Kshirsagar, Chair in Clinical Pharmacology, National Institute for
Research in Reproductive Health, Mumbai.
4. Dr. Chandishwar Nath, Scientist-G & Scientist –in-charge, Division of
Toxicology, Lucknow.
5. Dr. S. D. Seth, Advisor, Clinical Trials Registry, ICMR HQ, New Delhi
6. Dr. Rajni Kaul, Scientist-F, Division of BMS, ICMR HQ, New Delhi.
7. Dr. Bikash Medhi, Assoc. Prof. Dept of Pharmacology PGIMER,
Chandigarh.
From CDSCO:
1. Dr. V. G. Somani, Joint Drugs Controller (India).
2. Sh. R. Chandrashekhar, Deputy Drugs Controller (I), CDSCO (HQ).
3. Mrs. Rubina Bose, Deputy Drugs Controller (I), CDSCO (HQ).
Following members could not attend the meeting:
1. Dr. Deepak Kaul, Prof. & Head, Deptt. Of Experimental Medicine &
Biotechnology, PGIMER, Chandigarh.
2. Prof. Dinesh Puri, Head Department of Medical Bio-Chemistry, GTB
Hospital, Shahdara, Delhi.
3. Dr. S.K. Sharma, Prof. & Head, Deptt. of Medicine, AIIMS, New Delhi.
4. Dr.C.D. Tripathi, Prof. & Head, Deptt. of Pharmacology, VMMC, New Delhi
5. Dr. Vijay Kumar, Scientist ‘F’, Division of BMS-Co-Ordinator, ICMR HQ,
New Delhi.
Dr. V. G. Somani welcomed the members of the IND Committee. He then apprised
the Committee about the order of the Hon’ble Supreme Court of India, dated
21.10.2013 in the matter of W.P. (C) No. 33/2012 of Swasthya Adhikar Manch,
Indore & Anr Vs. Ministry of Health and Family Welfare & Ors. with WP(C) No.
779/2012 regarding clinical trials wherein it was directed that the Technical
Committee and the Apex Committee while evaluating the cases shall keep in view
all relevant aspects of safety and efficacy particularly in terms of assessment of risk
versus benefit to the patients, innovation vis-a-vis existing therapeutic option and
unmet medical need in the country.
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In view of this, Dr. V. G. Somani requested the members for their critical evaluation of
applications considering various scientific and ethical parameters of the proposal
specially all relevant aspects of safety and efficacy particularly in terms of
assessment of risk versus benefit to the patients, innovation vis-a-vis existing
therapeutic option and unmet medical need in the country. The minutes of the last
IND meeting held on 06.02.15, which was already circulated to the members were
taken as approved. Thereafter, firms’ representatives were asked to make
presentation of their respective proposals as per agenda.
Item No.1: Proposal of M/s. Torrent Pharmaceuticals Limited to conduct PhaseI clinical trial with TRC160334.
M/s. Torrent Pharmaceuticals Limited has applied for grant of permission to conduct
Phase-I clinical trial with TRC160334 entitled “A double blind, placebo controlled,
randomized, multiple dose, dose-ascending study to evaluate the safety, tolerability
and pharmacokinetics of TRC160334 after intravenous administration in patients at
risk of developing acute kidney injury”.
TRC160334 is a novel synthetic compound, which stabilizes Hypoxia Inducible
Factors (HIF) by inhibiting HIF hydrolyse enzymes to exploit HIFs properties of
helping cells to adapt and survive in a stressful microenvironment. Single ascending
doses of intravenous TRC160334 were evaluated in Phase-I (First in Man) study for
safety in healthy volunteers and elderly subjects with renal impairment. The study
was conducted by Biotrial, Rennes, France. During first in man study TRC160334
was found safe and well tolerated from dose 1 mg to 27 mg in 25 young healthy
subjects. Based on favourable safety and pharmacokinetic profile observed during
Phase-I (single ascending dose) study, TRC160334 is planned to be further
evaluated in Phase-I (multiple ascending dose) study to establish the safety and
tolerability of multiple intravenous doses of TRC160334 in patients at risk of
developing acute kidney injury.
Recommendations: The Committee deliberated the proposal in details and
observed that the current study is proposed in patients at risk of developing acute
kidney injury like diabetics, hypertensive etc., Therefore the Committee
recommended that the firm should either submit revised Phase-I clinical trial protocol
for conducting the study in healthy subjects or shall submit Phase-II clinical trial
protocol with the proposed inclusion exclusion criteria in the patients with age group
restricted up to 65 including specific efficacy endpoints along with safety. Present
study is appearing more as safety and tolerability studies in the Phase- II without
efficacy endpoint rather than Phase-I study in healthy volunteers.
Item No.2: Proposal of M/s Bharat Biotech International Limited to conduct
Phase-I clinical trial on Chikungunya Viral Vaccine.
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M/s Bharat Biotech International Ltd., Hyderabad has applied for grant of permission
to conduct Phase-I clinical trial on purified Chikungunya Viral Vaccine (Inactivated)
(Protocol No. BBIL/CHIV/2014) under the title “Phase-I open label, dose-escalation
clinical trial to evaluate the safety, tolerability and immunogenicity of Chikungunya
vaccine in healthy adults of 18 to 50 years age”.
Recommendations: After detailed deliberation the Committee recommended the
proposed Phase-I study subject to following conditions:1. The study shall be conducted in Phase-I study centre with necessary
emergency facilities.
2. Healthy volunteers shall be admitted 24 hrs before administration of dose and
shall be observed for 48 hrs post dose (in door) of Phase-I facilities.
3. All the volunteers shall not be administered the vaccine on same day, but over
a period of 7 days to ascertain the safety.
4. The 3 doses of the vaccine shall be administered at the prescribed interval of
7 days as per protocol.
Accordingly the firm shall make necessary amendment in the protocol and
submit to DCG (I) office for necessary action alongwith complete pre-clinical
toxicity study report.
Item No. 3: Proposal of M/s. Cadila Pharmaceuticals Limited to conduct Phase-I
clinical trial with CPL-2009-0031.
M/s. Cadila Pharmaceuticals Limited applied for the grant of permission to conduct
Phase I/II clinical trial with CPL-2009-0031 entitled “A safety pharmacokinetics and
pharmacodynamics study of CPL-2009-0031 in healthy volunteers and patients with
type-2 Diabeties Mellitus (T2DM)”.
The CPL-2009-0031 phosphate is a novel DPP-IV inhibitor that is proposed to be
used in the treatment of T2DM. Its activity profile in mice is similar to that of clinically
used DPP-IV inhibitors i.e Saxagliptin and Sitagliptin. While Saxagliptin and
Sitagliptin are α-aminoacid and β-aminoacid derivatives respectively, the CPL-20090031 incorporates both α-aminoacid and β-aminoacid in its structure.
The proposal was deliberated in the IND Committee meeting held on 08.01.2014 and
the Committee after detailed deliberation recommended that the following should be
submitted:1.
Repeat dose toxicity data generated in one non-rodent species of animal.
2.
Comparative PK study should be conducted with the Investigational product vs
Sitagliptin in rats.
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Firm has submitted 28 Day repeated-dose toxicity study carried out in Monkey
and Comparative PK study conducted with the Investigational product vs Sitagliptin in
rats. Firm has also submitted clarification for not conducting 24 weeks repeated dose
toxicity study.
Recommendations: After detailed deliberation the Committee recommended to
conduct Phase-I clinical trial in healthy volunteers as per stage-I of the protocol,
based on the 28 days repeat dose toxicity study report and comparative pK study
conducted with the Investigational product vs Sitagliptin in rats. Further toxicity
studies of duration as prescribed in Schedule-Y need to be carried out as the
molecule will go in further clinical developmental stages.
Item No. 4: Phase I (DDI Study) clinical trial with DS-5565 of M/s Sun Pharma
(earlier M/s. Ranbaxy Labs Ltd.).
M/s. Ranbaxy Labs Ltd. had applied for the grant of permission to conduct
Phase I (DDI Study) clinical trial with DS-5565 entitled “A phase I, three-part, threeperiod, open label, randomized, single dose, crossover, interaction study, in healthy
male subjects, to investigate the potential for a pharmacokinetic drug-drug interaction
after co-administration of DS-5565 and metformin”. The primary objective of the study
was to evaluate the effect of DS-5565 on the pK of metformin in human plasma. DS5565 is a potent and specific ligand of α2δ subunit of voltage-dependent calcium
channel in neuronal cells and other tissues. DS-5565 is being developed for the
treatment of neuropathic pain associated with diabetes peripheral neuropathy
(DPNP).
Based on the recommendation of IND Committee, Technical Committee and
Apex Committee, M/s Ranbaxy Labs Ltd. was granted permission to conduct the said
clinical trial. Firm has conducted the clinical trial on 21 subjects from 13.12.2013 to
05.02.2014. The firm concluded that there is no pharmacokinetic drug-drug
interaction between DS-5565 15mg and Metformin 850mg. Firm has submitted
clinical study report.
Recommendations: The Committee did not deliberate the proposal as the firm did
not present the Phase-I clinical study report before the Committee.
Item No. 5. Interim study report on first ten patients in Phase-II clinical trial of
SMRX-11 20 mg of M/s Symmetrix Biotech Pvt. Ltd.
M/s. Symmetrix Biotech was granted permission to conduct Phase II Clinical trial with
their indigenously developed “Clot Specific Streptokinase” (CSSK) on 19th Dec 2013
with following condition:
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1. Initially the dose of 10 mg & 20 mg should be tried. Based on the results from
the study, committee may consider the study with higher doses of 40, 50 &
80mg.
2. The subjects should be provided with information about all essential elements of
Patients Information sheet (as per Appendix V of Schedule Y to D & C Rules)
before his/her participation in the study.
As per the recommendation of IND committee, the firm has submitted interim report
of 10 Patients that were tested in their currently ongoing above mentioned (Phase II)
clinical trial up to the dose of 20 mg (10 mg & 20 mg) for review and approval for
further higher dose up to 80 mg.
Recommendations: After detailed deliberation the Committee recommended that
the firm shall conduct the proposed Phase-II study in dose less than 20 mg i.e with
10 mg and higher than 20 mg (with incremental increase of 10 mg i.e 30 mg, 40 mg)
to prove the ineffective dose and dose where maximum response (plateau of doseresponse relationship) is achieved, under proper review of DSMB. It was mentioned
by the sponsor that Phase-I with more than 20 mg dose with this product in healthy
volunteers have more risk, hence studies in Phase-II at higher dose are considered
in the patients. The results of the study after completion of the objective may be
brought to the IND Committee before conducting of further Phase-III (along with
proposed protocol if results justify further studies). Accordingly protocol etc., may be
modified and submitted.
Item No. 6. Import and marketing proposal of Diperoxochloric acid concentrate
solution of M/s Centaur Pharmaceuticals for topical use.
M/s. Centaur Pharmaceuticals Pvt. Ltd. has applied for import and marketing of
Diperoxochloric acid (DPOCL) topical solution to be reconstituted with sterile Sodium
Chloride solution BP 0.9% w/v (Cutaneous solution) and indicated for wound healing
in diabetic neuropathic ulcers of skin and subcutaneous tissues.
DPOCL is a new chemical entity with a mitogenic activity on fibroblasts, supporting
proliferation and also has an antibacterial property especially against gram-negative
germs, lasting longer than 24 hours. Repacking will be done at Centaur
Pharmaceuticals as bottle A in 10 ml bottle alongwith Sodium Chloride in 30ml bottle.
The drug is not approved anywhere in the world including exporting country,
Germany.
The firm has conducted phase-III clinical study, wherein the efficacy and safety of
DPOCL was investigated in over 300 patients suffering from diabetic foot ulcer in
comparison with active-control solution i.e. isotonic normal saline (0.9%). It is
reported that more than 90% of the patients treated with DPOCL had positive
response as compared to 66% of active-control (treatment response defined by at
least 50% wound reduction in 4 weeks).
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Phase-III clinical study report was deliberated in IND Committee held on 30.05.2014.
The Committee noted that less number of patients required the use of antibiotics and
reported faster healing in the test drug arm when compared to the comparator arm.
After deliberation the Committee recommended for the grant of permission for the
import and marketing of Diperoxochloric acid (DPOCL) along with sterile sodium
chloride solution BP 0.9% w/v (Cutaneous solution) in the country to be indicated for
wound healing in diabetic neuropathic ulcers of skin and subcutaneous tissues
subject to the condition that following is required to be submitted to the DCGI before
the grant of approval.
1.
Long term stability data of drug substance and formulation as per Appendix
IX of Schedule Y.
2. Stability testing of formulation after constitution or dilution as per Appendix IX
of Schedule Y.
The firm has submitted response to query related to stability data and animal toxicity
study. Further the firm mentioned that they have submitted wrong label earlier with
storage condition at 30ºC, whereas the corrected label is that the product to be
stored at 25ºC. The product is not yet approved in the exporting country.
Recommendations: The firm presented the stability report of DPOCL and that of the
reconstituted solution in normal saline. The stability study data presented was
examined and it was observed that the firm has submitted 14 days stability data of
reconstituted solution. The Committee asked the firm the reason for not conducting
the study for more than 14 days e.g 1 month or till it is stable to determine the
stability of the reconstituted solution to be used for diabetic foot ulcers which is
expected to be used for much longer time.
The Committee was of the opinion that the indication of the product should be wound
healing in diabetic foot ulcer instead of diabetic neuropathic foot ulcer. However as
the Phase III clinical trial conducted was for diabetic neuropathic foot ulcers,
therefore the Committee decided that the indication may not be revised at this stage.
Accordingly the Committee recommended that the firm is required to submit stability
study report of reconstituted solution for more than 14 days or till such time it is
actually stable (i.e,16 days, 17 days, 1 months etc.). The firm shall also revise their
Prescribing Information with following corrections:
1. Contraindication: It is contraindicated in patients hypersensitive to the
products.(rather than ingredient)
2. Drug Interactions: “Conducted over 400 patients” to be deleted and written as
the Phase-II and III clinical trials did not reveal any data towards drug-drug
interaction.
3. “Overdosage”: “Absorption is insignificant” shall be replaced indicating
“whether there is absorption or no absorption”.
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4. The maximum days allowed for storage after reconstitution at specific
temperature condition shall be specified.
5. Storage condition on the label shall match with the stability studies (i.e., below
25°C)
The Committee recommended for grant of permission to the Investigational
New Drug DPOCL for import of bulk and filling of formulation in India on
submission of revised package insert and details of stability studies as
proposed.
The meeting ended with vote of thanks to all the experts.
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Additional Agenda:Item No. 1. Request of M/s Pharmazz for waiver of Informed Consent (prior
making application to DCGI and IND for phase II clinical trial study) for clinical
trial on acute medical emergency indication of hypovolemic shock due to
excessive blood loss.
M/s. Pharmazz India Pvt. Ltd. had applied for the grant of permission to conduct
Phase-I study with PMZ-2010 (Centhaquin citrate) Injection 1mg/10ml entitled “A
randomized, double-blind, placebo-controlled Phase I study to determine the safety,
tolerability, pharmacokinetics and pharmacodynamics of single and multiple
ascending doses of PMZ-2010 in healthy male volunteers”.
The proposal was placed for deliberation in the meeting of the IND Committee held
on 29.04.2013 & 08.01.14. Accordingly, firm was issued clinical trial NOC to conduct
phase-I study.
Now, the firm has submitted a representation wherein the firm has stated that they
have completed the phase-I study and test drug PMZ-2010 was well tolerated and
found safe in healthy subjects.
The firm has also informed that they are in the process of filing Phase II application
for the clinical trial study titled as “A prospective, multicentric, randomized, double
blind, parallel, placebo controlled phase II safety and efficacy study of PMZ2010 as a
resuscitative agent for hypovolemic shock due to excessive blood loss to be used
along with standard shock treatment”. Subjects with hypovolemic shock due to blood
loss with systolic blood pressure <90mmHg will be provided standard treatment for
shock and PMZ-2010 or placebo (saline) will be administered only, if systolic arterial
blood pressure does not recover and remains <90mmHg after 10 minutes of standard
treatment for shock.
Patients to be enrolled in this study will be in a state of severe hemorrhagic shock
and therefore, unable to give their consent to participate in the study at the time of
randomization due to altered sensorium secondary hypotension, the severity of
injury, head injury, or potential intoxication with sedating drugs or alcohol. Moreover,
in such cases legal next-of –kin are usually not available to provide immediate
consent, nor is it practical for the medical emergency.
The firm has also informed that Informed Consent form will be obtained when either
the subject is in medically stable condition and is able to provide consent, or their
legally authorized representative (LAR) is available to give the consent. If subjects or
their legally authorized representative (LAR) deny the consent, subject will be
excluded from the study.
Based on the above facts, the firm has requested to consider their application for
waiver of Informed Consent for Phase II clinical trial on acute medical emergency
indication of hypovolemic shock due to excessive blood loss.
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Recommendations:- The Committee recommended that Informed Consent has to
obtained from legally acceptable representative in case subject is not in a condition
to give ICF. There are standard care available for such indication and the same may
be given in case informed consent cannot be obtained from such patients. The
Committee did not agree with the proposal for waiver of ICF. Further the Committee
wanted the firm to present.
Item No. 2. Issues raised by Smt. Maneka Sanjay Gandhi, Hon’ble Minister of
Women and Child Development regarding plight of animals undergoing preclinical/toxicity studies by Central Drugs Standard Control Organization.
This is with reference to letter of Smt. Maneka Sanjay Gandhi, Hon’ble Minister of
Women and Child Development, dated 03.07.2015 addressed to Sh. Jagat Prakash
Nadda, Hon’ble Minister of Health and Family Welfare, regarding plight of animals
undergoing pre-clinical/toxicity studies by Central Drugs Standard Control
Organization. It has been stated in the said letter that India being signatory of OECD
Council Act is under obligation to respect the data generated by other country
regarding pre-clinical/toxicity studies and therefore there is no need for CDSCO to
undertake further studies. This is a wasteful and expensive duplication. Animals are
killed, laboratory time is wasted, scientist’s time is wasted and it costs India a lot of
money. The molecules of interest have been those that are approved by multiple
regulatory agencies and have been through many animal studies which have been
made available on sites and published in scientific journals.
Thorough reports of all scientific articles, studies and published literature are always
given to the CDSCO along with the clinical trial applications. Unfortunately, under the
current regulations of item 4, Appendix-I of Schedule Y of Drugs and Cosmetics Act,
1940, additional tests on animals are then ordered. This is illegal in many ways:
1. It is violation of International treaty.
2. It is a violation of the prevention of Cruelty to Animal Act 1960 (17 d) which
orders that “experiments on animals are to be avoided whenever it is possible
to do so”.
3. It is a violation of CPCSEA (Committee for the Purpose of Control and
Supervision on Experimentation in Animals Control and Supervision rules
1998 Rule 9 (k) which states “no experiment the result of which is conclusively
known, shall be repeated without previous justification”.
4. It is in violation of a MOEF notification of 23.10.2006 amending Rule 2 (bb)
“Provided that replacement alternatives not involving experiments on animals
should be given due and full consideration and sound justification must be
provided in case alternatives, though available, are not used.”
Recommendations:- The Committee deliberated and agreed with the statement
mentioning that, for drugs approved in other countries where complete toxicological
data generated in GLP certified laboratory and in alignment with the requirements
prescribed under Drugs and Cosmetics Act, 1940 and Rules, 1945 (Schedule Y),
further toxicity study may not be required if complete data as per prescribed
requirements is submitted during application for new drug approval.
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It may also be explored, in line with international practices, to encourage the use of
other alternative methods than animal studies, wherever such robust validated
methods are available for small or large animals.
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