Serious Adverse Event Reporting and Compensation: Rule 122 DAB of Schedule Y As defined in schedule Y, SAE is an untoward medical occurrence during clinical trial that is associated with death, in patient hospitalization (in case the study was being conducted on out-patient), prolongation of hospitalization (in case the study was being conducted on in-patient), persistent or significant disability or incapacity, a congenital anomaly or birth defect or is otherwise life threatening [1]. The reporting timeline for all serious and unexpected adverse events by principal investigator is now within 24 hours of occurrence of event to the Licensing Authority, sponsor and the EC; whereas, prior to this amendment, the 24 hours reporting was limited to sponsor by the investigator. The detailed report of SAEs, after due analysis, should be forwarded by the investigator and sponsor to Chairman of the EC, Licensing Authority and the Head of the Institution within ten calendar days of occurrence of the SAEs. The report of SAEs of death, in addition, also needs to be forwarded to the Chairman of expert committee appointed by Licensing Authority [1]. Prior to the amendment, the SAEs management and reporting was done by Bioequivalence centers, but now sponsor also need to send a separate report after due analysis by their medical affairs team in cases of SAEs. Serious adverse event reports submitted to Licensing Authority should be in color coded binding, where the reports of SAEs of deaths are submitted in red cover, the reports of SAEs of injury other than deaths in blue cover and the remaining cases of SAE reports in white cover [2]. We have observed that most of the SAEs submitted by bioavailability and bioequivalence (BA/BE) centers are in white cover, as adverse events are already documented for generic products and can be medically managed. In case of any AE (adverse events) during the BA/BE study, subjects need to be provided free medical management as long as required and the expenses have to be borne by the sponsor of the study. In addition, sponsor or his representative needs to compensate subjects if the injury is clinical trial related, due to adverse effect of investigational product, violation of the approved protocol, scientific misconduct or negligence by the sponsor or his representative or by investigator, failure of investigational product to provide intended therapeutic effect, use of placebo in a placebo controlled trial, adverse effects due to concomitant medications, injury to a child in-utero due to participation of parents, or due to any clinical trial procedures [1]. Some of the above cases are not applicable to BA/BE studies like use of placebo and injury to child in-utero because these studies are conducted with marketed comparator and in healthy subjects only. Further BA/BE study centers already follow the practice of providing medical management of all AEs and SAEs whether related or not related. However, clarity on compensation amount in case of death or injury for healthy volunteer is required from the licensing authority. The final authority for determination of the cause of death or injury and also the quantum of compensation is now the Licensing Authority, who will communicate the compensation amount to sponsor within three months of receiving the report of SAE of death or injury. In case of SAEs of death, the expert committee shall provide its recommendation about causality and quantum of compensation to the licensing authority, and then the licensing authority shall pass the final order [1].
The sponsor has to pay the compensation in case of clinical trial related injury or death within thirty days of the receipt of order from Licensing Authority. In case the sponsor fails to provide medical management and / or financial compensation, the Licensing Authority may take necessary action as per rule, including suspension or cancellation of the clinical trial and/or restrict sponsor including his representative(s) to conduct any further clinical trials in India [1]. These changes have also led to requirement of changes in the Informed Consent Documents (ICD) where additional information should be incorporated mentioned in amendments. As per the new requirements in Appendix V of Schedule Y, now, the ICD should clearly state that the subject is entitled to free medical management as long as required in case of injury, and financial compensation in case of clinical trial related injury or death. The investigator will have to clearly inform the subject about his right to claim compensation in case of trial related injury or death, and to contact the sponsor / representative directly for any claim related queries. The contact details of sponsor representative should be provided in the ICD. In order to aid the calculation of compensation amount, the ICD now should have further details about the subject like qualification, occupation, annual income, address, and contact details of the nominee and his/her relation with the subject. A copy of ICD should be provided to subject and same should be mentioned in the ICD document [1].
Permission to Conduct Clinical Trials: Rule 122 DAC of Schedule Y Rule 122 DAC basically discusses about the compliance to regulatory and ethical guidelines for data submitted for clinical trials, and actions taken in case of noncompliance. Licensing Authority may inspect sponsor including their employees, subsidiaries, and branches, their agents, contractors, subcontractors, clinical trial sites, BA/BE centers and investigators to verify the compliance and they should provide adequate replies to the inspectors in relation to conduct of clinical studies. Licensing Authority may reject or cancel studies and debar investigators, sponsors including their employees, subsidiaries and branches, their agents, contractors and subcontractors for conduct of any clinical trials in future [3]. It is very important that each stakeholder understands his/ her responsibility and complies strictly with the regulatory requirements where need of understanding of good clinical practice (GCP) and training arises for all stakeholders.
Ethics Committee Registration and Functioning: Rule 122 DD of Schedule Y With introduction of Rule 122 DD in Schedule Y, prior registration of ECs with DCGI is mandatory to review and accord its approval to a clinical trial protocol. The registration is given for a period of three years to the committees from the date of issue, unless suspended or cancelled [4]. Now all BA/BE study protocols need to be reviewed and approved by a registered Independent EC from same location as that of the BA/BE center. Of the additional responsibilities given to the Ethics Committees, one of the major responsibility is forwarding it’s report on the serious adverse event of injury, after due analysis with causality assessment and opinion on financial compensation to the licensing authority within twenty one calendar days of the occurrence of the event, and in cases of SAE of death report should also be sent to Chairman of the expert committee [5]. The expert committee and licensing authority are mainly considering the EC’s opinion to decide on the relatedness and quantum of compensation. Currently there is lack of clarity from CDSCO on guidelines for calculation of compensation amount; the ECs are thus having a tough time giving their opinion on compensation amount. ECs are now required to maintain all clinical trial documents reviewed by them for at least five years and be open for inspections by licencing authority at the EC office.
So far, about 500 ECs have been registered with CDSCO and about 60 of them are independent ECs [6]. The registration of independent ECs has been initiated after a long waiting period and many of them got query letter due to stringent scrutiny of their applications. But the independent ECs can review only the study protocols and related documents of BA/BE studies of approved products. So BA/BE centers now need to approach institutional ECs for approval of BE study protocols of drug products not yet approved in India. Also, many BA/ BE centers also conduct phase I pharmacokinetic studies along with BA/BE studies. Even for such phase I studies, the BA/BE centers will have to approach Institutional ECs, since Independent ECs will not be able to take up review of such studies. The biggest challenge will arise when the institutional ECs also reject such proposals which are not conducted in their institute / site.
Impact of Current Regulatory Changes on BA/BE Industry of India The requirements for BA/BE studies are becoming similar as for clinical trials and pose challenges in front of BA/BE centers. The regulatory authority may start asking statistical justification for number of subjects in BE study. Many processes, which earlier only required notification now need approval, for e.g., all protocol amendments, change of BA/BE study center. Earlier, BE for export studies were approved for the products which are even not approved and marketed in India but it may not be the case now. There is need to revise the existing SOPs and other study BA/BE documents, as per the new amendments for SAEs’ reporting timelines and compensation. This may lead to some delays in the completion of the existing studies. However, considering the slowdown in the global clinical trials, the Indian pharma industry will again focus on generic business and number of BA/BE studies may increase both for registration in India and also for export.
Serious Adverse Event Reporting and Compensation:
ReplyDeleteRule 122 DAB of Schedule Y
As defined in schedule Y, SAE is an untoward medical occurrence
during clinical trial that is associated with death, in patient
hospitalization (in case the study was being conducted on out-patient),
prolongation of hospitalization (in case the study was being conducted
on in-patient), persistent or significant disability or incapacity, a
congenital anomaly or birth defect or is otherwise life threatening [1].
The reporting timeline for all serious and unexpected adverse
events by principal investigator is now within 24 hours of occurrence
of event to the Licensing Authority, sponsor and the EC; whereas, prior
to this amendment, the 24 hours reporting was limited to sponsor
by the investigator. The detailed report of SAEs, after due analysis,
should be forwarded by the investigator and sponsor to Chairman of
the EC, Licensing Authority and the Head of the Institution within ten
calendar days of occurrence of the SAEs. The report of SAEs of death,
in addition, also needs to be forwarded to the Chairman of expert
committee appointed by Licensing Authority [1].
Prior to the amendment, the SAEs management and reporting was
done by Bioequivalence centers, but now sponsor also need to send a
separate report after due analysis by their medical affairs team in cases
of SAEs.
Serious adverse event reports submitted to Licensing Authority
should be in color coded binding, where the reports of SAEs of deaths
are submitted in red cover, the reports of SAEs of injury other than
deaths in blue cover and the remaining cases of SAE reports in white
cover [2]. We have observed that most of the SAEs submitted by
bioavailability and bioequivalence (BA/BE) centers are in white cover,
as adverse events are already documented for generic products and can
be medically managed.
In case of any AE (adverse events) during the BA/BE study, subjects
need to be provided free medical management as long as required and
the expenses have to be borne by the sponsor of the study. In addition,
sponsor or his representative needs to compensate subjects if the injury
is clinical trial related, due to adverse effect of investigational product,
violation of the approved protocol, scientific misconduct or negligence
by the sponsor or his representative or by investigator, failure of
investigational product to provide intended therapeutic effect, use of
placebo in a placebo controlled trial, adverse effects due to concomitant
medications, injury to a child in-utero due to participation of parents,
or due to any clinical trial procedures [1]. Some of the above cases
are not applicable to BA/BE studies like use of placebo and injury to
child in-utero because these studies are conducted with marketed
comparator and in healthy subjects only. Further BA/BE study centers
already follow the practice of providing medical management of all
AEs and SAEs whether related or not related. However, clarity on
compensation amount in case of death or injury for healthy volunteer
is required from the licensing authority.
The final authority for determination of the cause of death or
injury and also the quantum of compensation is now the Licensing
Authority, who will communicate the compensation amount to
sponsor within three months of receiving the report of SAE of death
or injury. In case of SAEs of death, the expert committee shall provide its recommendation about causality and quantum of compensation to
the licensing authority, and then the licensing authority shall pass the
final order [1].
The sponsor has to pay the compensation in case of clinical trial
ReplyDeleterelated injury or death within thirty days of the receipt of order from
Licensing Authority. In case the sponsor fails to provide medical
management and / or financial compensation, the Licensing Authority
may take necessary action as per rule, including suspension or
cancellation of the clinical trial and/or restrict sponsor including his
representative(s) to conduct any further clinical trials in India [1].
These changes have also led to requirement of changes in the
Informed Consent Documents (ICD) where additional information
should be incorporated mentioned in amendments. As per the new
requirements in Appendix V of Schedule Y, now, the ICD should
clearly state that the subject is entitled to free medical management as
long as required in case of injury, and financial compensation in case of
clinical trial related injury or death. The investigator will have to clearly
inform the subject about his right to claim compensation in case of
trial related injury or death, and to contact the sponsor / representative
directly for any claim related queries. The contact details of sponsor
representative should be provided in the ICD. In order to aid the
calculation of compensation amount, the ICD now should have further
details about the subject like qualification, occupation, annual income,
address, and contact details of the nominee and his/her relation with
the subject. A copy of ICD should be provided to subject and same
should be mentioned in the ICD document [1].
Permission to Conduct Clinical Trials: Rule 122 DAC
ReplyDeleteof Schedule Y
Rule 122 DAC basically discusses about the compliance to
regulatory and ethical guidelines for data submitted for clinical trials,
and actions taken in case of noncompliance. Licensing Authority may
inspect sponsor including their employees, subsidiaries, and branches,
their agents, contractors, subcontractors, clinical trial sites, BA/BE
centers and investigators to verify the compliance and they should
provide adequate replies to the inspectors in relation to conduct of
clinical studies. Licensing Authority may reject or cancel studies and
debar investigators, sponsors including their employees, subsidiaries
and branches, their agents, contractors and subcontractors for conduct
of any clinical trials in future [3]. It is very important that each
stakeholder understands his/ her responsibility and complies strictly
with the regulatory requirements where need of understanding of good
clinical practice (GCP) and training arises for all stakeholders.
Ethics Committee Registration and Functioning: Rule
ReplyDelete122 DD of Schedule Y
With introduction of Rule 122 DD in Schedule Y, prior registration
of ECs with DCGI is mandatory to review and accord its approval to
a clinical trial protocol. The registration is given for a period of three
years to the committees from the date of issue, unless suspended or
cancelled [4]. Now all BA/BE study protocols need to be reviewed and
approved by a registered Independent EC from same location as that
of the BA/BE center.
Of the additional responsibilities given to the Ethics Committees,
one of the major responsibility is forwarding it’s report on the serious
adverse event of injury, after due analysis with causality assessment and
opinion on financial compensation to the licensing authority within
twenty one calendar days of the occurrence of the event, and in cases of SAE of death report should also be sent to Chairman of the expert
committee [5]. The expert committee and licensing authority are mainly
considering the EC’s opinion to decide on the relatedness and quantum
of compensation. Currently there is lack of clarity from CDSCO on
guidelines for calculation of compensation amount; the ECs are thus
having a tough time giving their opinion on compensation amount.
ECs are now required to maintain all clinical trial documents reviewed
by them for at least five years and be open for inspections by licencing
authority at the EC office.
So far, about 500 ECs have been registered with CDSCO and about
ReplyDelete60 of them are independent ECs [6]. The registration of independent
ECs has been initiated after a long waiting period and many of them
got query letter due to stringent scrutiny of their applications. But
the independent ECs can review only the study protocols and related
documents of BA/BE studies of approved products. So BA/BE centers
now need to approach institutional ECs for approval of BE study
protocols of drug products not yet approved in India. Also, many BA/
BE centers also conduct phase I pharmacokinetic studies along with
BA/BE studies. Even for such phase I studies, the BA/BE centers will
have to approach Institutional ECs, since Independent ECs will not be
able to take up review of such studies. The biggest challenge will arise
when the institutional ECs also reject such proposals which are not
conducted in their institute / site.
Impact of Current Regulatory Changes on BA/BE
ReplyDeleteIndustry of India
The requirements for BA/BE studies are becoming similar as
for clinical trials and pose challenges in front of BA/BE centers.
The regulatory authority may start asking statistical justification
for number of subjects in BE study. Many processes, which earlier
only required notification now need approval, for e.g., all protocol
amendments, change of BA/BE study center. Earlier, BE for export
studies were approved for the products which are even not approved
and marketed in India but it may not be the case now. There is need
to revise the existing SOPs and other study BA/BE documents, as per
the new amendments for SAEs’ reporting timelines and compensation.
This may lead to some delays in the completion of the existing studies.
However, considering the slowdown in the global clinical trials,
the Indian pharma industry will again focus on generic business and
number of BA/BE studies may increase both for registration in India
and also for export.