Regulatory Legislation and Guidelines for Recombinant Drugs, Pharmaceuticals and Biologicals

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Regulatory Legislation and Guidelines for
Recombinant Drugs, Pharmaceuticals and
Biologicals K.K. Tripathi Department of
Biotechnology (Ministry of Science and
Technology), Government of India, New
Delhi The views expressed in the presentation
are those of the individual and thy have nothing
to do with the organization with which he is
associated
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• Biotech Industry and rDNA Research
• Indian Companies in modern biotechnology
• Over 900 companies operating in all sectors of
  biotechnology,
• Biopharmaceuticals- gt49
• Transgenic Crops/Seeds- gt60
• Industrial Products- 15 (Probiotics, Enzymes)
• Indian Institutions in modern Biotech Research
• Over 90 Institutions engaged in rDNA Research
• Public Funded Institutions- gt57
• Private Institutions (Teaching Research)- gt37
• Universities- gt115
• Total number of organisations involved in rDNA
  Research- 256

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• A TYPICAL CASE OF STAKEHOLDERDS INTERACTION
• SHAPING THE FUTURE OF TRANSGENICS
• Central government - want to enforce EP Act
  through sate governments as per biosafety
  guidelines
• Politicians - want protection of public
  interests and safety of environment with
  punishment to guilty as per Law
• Public general seeks information and are more
  concerned for future with benefits and risks of
  rDNA products
• Scientists - want to set an example by providing
  more products with modern biotech research
• Media want report regularly and views of all
  without wrong interpretations
• Ihdustry - request to protect their investment
  and enforce law at the same time
• Consensus is building on to protect public
  interest, punish guilty and ensure maximum safety
  to environment with no (relatively low) risk !!!

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The public should be viewed as a partner and a
level of trust needs to be created. Developing
this style will be a major challenge for business
leaders as well as university/industry scientists
and government regulators. The Public perception
is most important in the success/failure of rDNA
product and safety aspects to environment/humans/a
nimals etc.
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• Why Regulations are Necessary for Using GMOs and
• Products Thereof?
• GMOs and and their products are to play important
  role including human and animal health care
  system, agriculture, industrial products,
  environment management
• Concurrently, there could be unintended hazards
  and risks from the use of GMOs and products
  thereof, if the new technology was not properly
  assessed before use
• A GMO can be safe but this can be unsafe too
  depending upon the trans-genes, the host organism
  and the environment where the GMO is being tested
• GMOs can be microorganisms, plants, and animals

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• GENETICALLY MODIFIED ORGANISMS (GMOs) AND
• r-DNA PRODUCTS GOVERNED BY
• Environment (Protection) Act, 1986
• - Rules, 1989 of EPA
• Industries (Development Regulation) Act, 1951
• - New Industrial Policy Procedures, 1991
• - EXIM Policy
• Drugs Cosmetics Act, 1940
• - Rules 1945
• Pharmaceutical Policy 2002

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Indian EPA implementation structure for GMOs
(1989 RULES) In order to contain possible
hazards to environment from the release of GMOs,
the Ministry of Environment and Forests has
notified in December 1989, the Rules for the
manufacture, use, import, export and storage of
hazardous Micro-organisms/ Genetically Engineered
Organisms or Cells under the Environment
(Protection) Act (EPA)1986.
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• APPLICATIONS OF 1989 RULES
• Manufacture, import and storage of microorganisms
  and gene technological products
• Genetically engineered organisms/ microorganisms
  and cells and correspondingly to any substance
  and products and food stuffs, etc., of which such
  cells, organisms or tissues form part
• New gene technologies in addition to cell
  hybridization and genetic engineering

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• STATUTORY BODIES
• The Recombinant DNA Advisory Committee (RDAC)
• Institutional Biosafety Committee (IBSC)
• Review Committee on Genetic Manipulation (RCGM)
• Genetic Engineering Approval Committee (GEAC)
• State Biotechnology Coordination Committee (SBCC)
• District Level Committee (DLC)

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• INSTITUTIONAL BIOSAFETY COMMITTEE (IBSC)
• Constituted by an occupier or any person
  including RD institutions handling GMOs
• Comprises Head of Institution, scientist doing
  rDNA work, medical expert and DBT nominee
• Assists the occupier or any person including RD
  institution prepare an emergency plan as per
  guidelines of RCGM
• Copies of emergency plan to be made available to
  District Level Committee/State Biotechnology
  Coordination Committee and the Genetic
  Engineering Approval Committee (GEAC)

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• REVIEW COMMITTEE ON GENETIC MANIPULATION (RCGM)
• RCGM is functioning in the Department of
  Biotechnology. Its functions are
• To review the reports in all approved/ongoing
  projects involving high risk category and
  controlled field experiments research in four
  areas namely human and animal healthcare,
  agriculture, industry and environmental
  management.
• To visit site of experimental facilities
  periodically where projects with biohazard
  potential are being pursued and also at a time
  prior to the commencement of the activity to
  ensure that adequate safety measures are taken as
  per the guidelines.
• To issue clearance for import/export of etiologic
  agents and vectors, germplasms, organelle, etc.
  needed for experimental work/training and
  research.

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• GENETIC ENGINEERING APPROVAL COMMITTEE (GEAC)
• The GEAC is functioning under the Ministry of
  Environment and Forests to examine and issue the
  clearance from the view point of environmental
  safety on a case by case basis for
• Activities involving large scale use of hazardous
  micro-organisms and recombinants in research and
  industrial production from environmental angle.
• Proposals relating to the release of genetically
  engineered organisms and products into the
  environment including experimental field trials.

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• IN ORDER TO EVALUATE PROPOSALS, DBT HAS ISSUED
  FOLLOWING GUIDELINES
• Recombinant DNA Safety Guidelines, 1990
• Recombinant DNA Safety Guidelines and
  Regulations, 1994
• Revised Guidelines for Safety in Biotechnology,
  1994
• Revised Guidelines for Research in Transgenic
  Plants, 1998
• Guidelines for generating pre-clinical and
  clinical data for rDNA vaccines, diagnostics and
  other Biologicals, 1999.
• Revision of Guidelines is a continuous process

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General approval procedures for recombinant
products Proposal Institutional Biosafety
Committee with DBT Nominee RCGMs
approvals Based on the pre-clinical trial data,
RCGM conveys its recommendations to the applicant
and copy to the DCG(I) and to GEAC RDAC approves
the protocol and recommends for conducting human
clinical trials  IBSC examines the human
clinical trial data and sends it for RCGM and DCG
(I) for Recommendation to GEAC for environmental
release GEAC approval for Environmental Release
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The applicant is to follow the provisions of the
Drugs Act for commercial release of the product.
This shall include inspection of the production
facilities, according temporary license to
produce trials batches, sending products from 5
trial batches to CRI, Kasauli or CDL, Kolkata,
receiving the test report by DCG (I) and finally
granting approval to manufacture and marketing
the product. Both DCG (I) and GEAC can impose
conditions of surveillance on the product during
marketing. Marketing under EPA can be for a
period of two to four years initially and this
can be renewed on the basis of an application.
Post-market surveillance data may be required to
be generated and submitted to DCG (I) and GEAC by
the applicants
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SUGGESTED MMODIFICATION IN THE STEPS Proposal Inst
itutional Biosafety Committee with DBT Nominee
RCGMs approvals Based on the pre-clinical data,
RCGM conveys its recommendations to the applicant
(copy to the DCG (I) for further n.a. and to GEAC
for information) RDAC/DCG(I) approves the
protocol and recommends for conducting human
clinical trials DCG(I) Examines the Human
Clinical Trials data and Recommends to GEAC
directly GEAC approval for Environmental/Commer
cial Release
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The Mashelkar Committee Inter-Ministerial
Committee setup by The Ministry of Environment
Forests New Delhi Report on Recombinant
Pharma Sector (Discussed on January 23, 2005)
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Recommendations of the Task Force on r-Pharma

• The step-wise regulatory procedures/protocols for
  Regulation of Recombinant Pharma Products
  derived from Living Modified Organisms (LMOs).
• Time lines for approvals.
• Recommendations on other Linked issues.
• Inter-ministerial Standing Committee on
  Biotechnology Regulation.
• Proposed independent institutional mechanism -
  National Biotechnology RegulatoryAuthority/Commiss
  ion.

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The step-wise regulatory procedures /protocols
for five categories
Protocol-IIndigenous product development,
manufacture and marketing of pharmaceutical
products derived from LMOs but the end product
is not a LMO. Protocol-IIIndigenous product
development, manufacture and marketing
pharmaceutical products where the end product
is a LMO. Protocol-IIIImport and marketing of
LMOs as Drugs/Pharmaceuticals in finished
formulations where end-product is a LMO.
Protocol-IVImport and marketing of LMOs as
Drugs/Pharmaceuticals in bulk for making finished
formulation where end product is a
LMO. Protocol-VImport and marketing of products
derived from LMOs as Drugs/Pharmaceuticals and
bought in bulk and/or finished formulations
where end product is not a LMO.
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Protocol I Indigenous product development
derived from LMOS but end product not a LMO.
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Protocol I Indigenous product development
derived from LMOs but end product
is not a LMO.

• As per the new recommendations, (i) GEAC has no
  role in the regulation of LMOs falling under Risk
  Group 1 II (ii) GEAC has no role in the
  approval of Phase-III clinical trials for risk
  group III above
• Amendment of Rule 1989 is not required in respect
  of (i) as MoEF may exercise the provisions of
  exemption under rule 20 which states The
  Ministry of Environment and Forests shall,
  wherever necessary, exempt an occupier handling a
  particular microorganism/genetically engineered
  organism from rule 7-11 . Accordingly LMOs
  falling under risk Group 1 II may be exempted
  from GEAC clearance.
• Further, the specific provision stipulating prior
  approval of GEAC for human clinical trials in
  recombinant pharma products are contained in the
  1999 DBT Guidelines for Generating Pre-Clinical
  Data for r-DNA Based Vaccines, Diagnostics and
  other Biologicals. Since there is no role of the
  GEAC for Phase-III clinical trials in case of
  therapeutic proteins, the DBT guidelines need to
  be suitably amended.
• Under Protocol I there is no change in the role
  of RCGM and DCGI.

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Protocol II Indigenous Product development
where end Product is a LMO
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A
Protocol II Contd.
HUMAN CT conducted
GEAC (examines environmental risk versus benefits
and accords approval for environmental release
under Rule 1989)
DCGI (approves Market Authorization under Drugs
Cosmetics Rules based on clinical trials data)
DCGI (Post Release Monitoring)
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Protocol III Import and marketing of LMOs as
drugs in finished formulations
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Protocol IV Import of LMOs as drugs in bulk for
making finished formulations.
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Protocol IV Contd.
A
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Protocol V Import and marketing of products
derived from LMOs as Drugs and bought in bulk
and/or finished formulations.
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Protocol V Import and marketing of products
derived from LMOs as Drugs and bought in bulk
and/or finished formulations.

• As per the new recommendations, (i) GEAC has no
  role in the import of recombinant therapeutic
  proteins as drugs. (ii) RCGM to give their
  comments on the import proposal to DCGI.
• Amendment of Rule 1989 is not required to
  accommodate the proposed change as we MoEF may
  exercise the provisions of exemption under rule
  20 which states The Ministry of Environment and
  Forests shall, wherever necessary, exempt an
  occupier handling a particular microorganism
  /genetically engineered organism from rule 7-11.
  Accordingly the import of recombinant drugs where
  the end product is not a LMO may be exempted from
  GEAC clearance.
• DCGI is of the view that in Protocol V the word
  after obtaining the views of RCGM to be
  deleted. They have suggested that RCGM function
  to be combined with RDAC under the office of
  DCGI. This would require a major amendment to
  Rules 1989.

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Time lines for approvals

• RCGM approval for pre-clinical animal studies
  45 days
• RDAC approval for Human Clinical Trials
  protocol 45 days
•  
• RDAC (DCGI) examination of trial data and
  approvalCase specific
• Simultaneous DCGI GEAC approvals 45 days
• GEAC approval procedure will be compliant with
  the Good Practices in Environmental Regulation
  adopted by MoEF.

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• Other Recommendations
• The products emanating from mono-clonals derived
  from rDNA technology in the form of therapeutic
  proteins/drugs would attract the provisions of
  Rule 1989 of EPA, and can be treated under
  Protocol I as Risk Category I II.
• If there is a change in the host organism or
  expression construct, fresh permission will be
  required to be sought from RCGM for the change by
  providing adequate data on bio-equivalence. If
  the data is found to be inadequate then RCGM may
  prescribe limited pre-clinical and/or clinical
  studies to be conducted to establish
  bio-equivalence. This would also be applicable to
  finished imported products intended for marketing.

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• Other Recommendations (contd)---
• No imported recombinant pharma product should be
  allowed to be introduced in the Indian market
  without adequate evaluation of clinical trial
  data or clinical evaluation in the Country. The
  Task Force recommends that the efficacy and
  safety of the imported product should be
  evaluated for its efficacy on the Indian
  population before issue of market authorization.
  
• For import of GMO / LMO for research/contract
  manufacturing or similar service, where the
  product (which is not an LMO) is to be exported
  out of India, a procedure should be laid down so
  that the companies can explore opportunities for
  this business while the safety aspect is also
  adequately addressed. A suggested procedure is
  IBSC to examine proposal and recommend to RCGM
  RCGM to approve if within Risk Group I and II.
  If organism is of Risk Group III or above, GEAC
  permission will be required. DCG(I) need not
  play any role.

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• Other Recommendations (contd)---
• Enzymes /industrial products from GMOs would
  attract the provisions of Rule 1989 of EPA. In
  such cases, RCGM may be authorized to approve
  such proposals under intimation to GEAC.
• The expertise in the various regulatory agencies
  under Rules 1989 of EPA should be further
  strengthened.
• There is a need for creation of an independent
  inspection facility to audit the manufacturing
  and containment facilities set up by the
  applicants involved in the production of
  recombinant drugs. This would also ensure
  acceptability of the Indian r-DNA pharmaceutical
  products in the global market. Since there is no
  single agency with adequate field level support
  system to carry out an independent inspection,
  the Task Force recommends that the Government may
  set up a separate agency for this purpose.
• On the issue of seeking approvals of
  PPA/DCGI/GEAC under Rules 1989 of EPA and PQO by
  Customs Authorities on the imports of
  microorganisms, GMOs/ LMOs for RD purpose it
  is suggested that the earlier practice of
  permitting the import with the approval of RCGM
  should continue and PPA/DCGI to issue
  instructions to Custom Authorities to clear the
  consignment based on RCGM approval.

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Inter-ministerial Standing Committee on
Biotechnology Regulation Constitution of a
standing inter-ministerial committee to redress
and look into various regulatory aspects and make
issue-based recommendations on case-by-case
basis. Prior to any deviation from the proposed
regulatory mechanism, which when comes in vogue,
the views of this inter-ministerial committee
should be obtained in the first instance. The
suggested composition of the committee is as
follows Chairman -To be an Eminent
Scientist Chairman, GEAC -Member Chairman,
RCGM -Member Member-Secretary,
GEAC -Member Member-Secretary,
RCGM -Member Joint Secretary (Seeds),
MoA -Member DDG, ICAR (Crop Sciences) -Member
Joint Secretary (MoEF) -Member Joint Secretary
(Food Processing) -Member Adviser (Industry,
DBT) -Member DG/Representative
(ICMR) -Member DCG(I) -Member Experts on
Immunobiologicals, Biogenerics, Plant Breeding,
Molecular Biology, Environmental Sciences and
other relevant areas may be co-opted from time to
time.
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• National Biotechnology Regulatory Authority/
  Commission
• Alternate models of a National Biotechnology
  Regulatory Authority
• Amendment of EPA and harmonization Seeds Act/
  Drugs Cosmetics Rules/ PFA Act may be necessary
  to obviate the approvals required under these
  statues.
• Harmonization is an essential prerequisite for
  establishing the national biotechnology
  regulatory authority.
• Recommended an inter-ministerial group to examine
  the model proposed and make specific proposals
  with respect to the implementation including the
  budgetary requirements.

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Capacity Building and its Relevance Capacity
building needs are considered to be the key
milestones to be successfully crossed by the
developing regions including at least some
developing countries in the region to enable the
confidence building exercise. In other words
there should be societal acceptance of the
technologies of living modified organisms (LMOs)
and in this context capacity building needs
become most relevant aspect in the safe use of
LMOs
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• Institution Building
• Risk assessment capacities
• Involvement of stakeholders
• Development and strengthening of legal and
  regulatory structures
• Capacity Building Efforts- Indian expertise and
  experience that can be shared in the region
• Skills in biotechnology process and applications
• Human resources strengthening and development

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