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REGULATORY ENVIRONMENT IN INDIA

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REGULATORY ENVIRONMENT IN INDIA Powered By Docstoc
					Regulatory
Considerations
for Conducting
Clinical Trials
In India
By Mukesh Kumar, PhD & Surinder Kher, MD


                In the last few years, there has been increasing
                interest in the pharmaceutical industry in out-
                sourcing drug discovery and clinical development
                programs to Asia, particularly India. Since clinical
                development accounts for about two-thirds of
                the total cost of developing a new drug, off-shor-
                ing clinical trials offers unique opportunities,
                especially in terms of access to study subjects,
                trained personnel, lower-cost infrastructure and
                labor pools. It has been widely recognized that
                India offers unique opportunities for conducting
                clinical trials due to a significant cost reduction
                and increased speed and productivity of all R&D
                phases required to bring a safe and effective drug to
                market. India has a large patient pool, well-trained
                and enthusiastic investigators, premier medical
                institutions, low per-patient trial cost and a highly   fourth largest producer of bulk drugs and home
                favorable regulatory climate. It is estimated that as   to the largest number of US Food and Drug
                much as 20% of all global clinical trials might be      Administration (FDA) approved manufacturing
                conducted in India by 2010.1 However, emerging          plants outside the US, India’s clinical development
                opportunities in India for clinical development         industry is still in its infancy. Although some
                are not without challenges especially in terms of       clinical trials have been conducted in India by and
                quality control measures, availability of trained       for global pharmaceutical industry and Indian
                professional resources, regulatory timeline predict-    academia for almost 15 years, the total number
                ability and data protection.                            of clinical trials is significantly low compared to
                     Despite being at the forefront of generic drug     those conducted in the US and European Union.
                production for several years, being the world’s         Regulations governing the conduct of clinical


26 March 2007
trial have not been well defined and primarily       with US and international standards, and plans
focused on generic drugs. Universal regulatory       are afoot to create a regulatory body in line
guidelines like those published by FDA have not      with FDA, a central authority governing all drug
been adopted, leading to diverse interpretation of   development-related activities. Indian regulatory
Indian regulations.                                  agencies are increasingly interacting with clinical
     In the last two years, India’s business and     development professionals to understand the
regulatory climate has undergone dramatic change.    caveats of old regulations and possible remedies.
In December 2004, Indian patent law was modified     In addition to the primary concern about the
to harmonize it with international laws govern-      safety of clinical trial subjects, Indian regulatory
ing intellectual property protection. Regulatory     authorities need to address several other issues in
processes are also being updated to harmonize        developing regulatory guidelines, such as cultural


                                                                                                            RA focus 27
            “Regulatory processes are also being updated to
                          and plans are afoot to create a reg
                 differences, language considerations, investigator       •   coordinating the activities of the States
                 training, etc.                                               and advising them on matters relating
                                                                              to uniform administration of the Act
                 History of Indian Drug Regulations                           and Rules in the country
                 Various regulatory aspects related to drug import,
                 manufacture, sale and advertising in India are           Despite the Act’s long history, nonuniformity in
                 covered under the Drugs & Cosmetics Act of 1940          interpreting and implementing the provisions of
                 and the ensuing Drugs & Cosmetics Rules of 1945,         laws have made it necessary to update the regula-
                 the Pharmacy Act of 1948 and the Drugs & Magic           tions to bring them up to par with international
                 Remedies (Objectionable Advertisements) Act of           standards. Historically, regulations have developed
                 1954. Of these, the Drug & Cosmetic Act (Act) of         mostly de novo, without much interaction with
                 1940, which led to the Drugs & Cosmetics Rules           international regulatory agencies. The Act has
                 (Rules) of 1945, is central legislation that regulates   been reviewed by several government advisory
                 India’s drug and cosmetic import, manufacture,           committees since the 1980s, who reached the
                 distribution and sale. The Act’s main objective          conclusion that the legislation is reasonably well-
                 is to ensure that available human drugs are safe         drafted but its enforcement had been weakened by
                 and efficacious and conform to prescribed quality        poor guidelines and variable regulatory personnel
                 standards, and marketed cosmetics are safe for           interpretation.
                 use. Over the years, the Act has been amended                 After several years of deliberations by vari-
                 several times to address public concerns. The            ous advisory committees, the Indian government
                 Central Drugs Standard Control Organization              plans to strengthen CDSCO and the office of the
                 (CDSCO), headed by the Drugs Controller General          DCG(I) and considerably expand and reorganize
                 (India) (DCG(I)), discharges the functions allocated     CDSCO along the lines of FDA within the next
                 to the Central Government (similar to the US             year or two. DCG(I), along with the Indian Council
                 Federal Government) under the Act. CDSCO is              of Medical Research (ICMR) have adopted inter-
                 attached to the office of the Director General of        national regulatory guidelines and issued Indian
                 Health Services in the Federal Ministry of Health        versions of the same. ICMR issued the Ethical
                 and Family Welfare. The DCG(I) has statutory             Guidelines for Biomedical Research on Human
                 authority under the Act with port offices, zonal         Subjects in 2000 and Indian GCP guidelines were
                 offices and drug testing laboratories. The DCG(I)’s      released by CDSCO in December 2001. The Drug
                 office is primarily responsible for:                     Technical Advisory Board (DTAB), the highest
                 • approval of new drugs to be introduced                 technical body under the Drugs & Cosmetics
                      in the country                                      Act, has endorsed adoption of GCP guidelines for
                 • permission to conduct clinical trials                  streamlining clinical studies in India.
                 • registration and control of imported
                      drug quality                                        Current Regulatory Processes
                 • developing regulatory measures and                     Clinical trials in India are regulated by Schedule Y
                      amendments to acts and rules                        of the Drug and Cosmetics Rules, 1945. The Rules
                 • establishing standards for drugs, cos-                 were revised in 2005 and the current rules, the
                      metics, diagnostics and devices and                 Drugs and Cosmetics (IInd Amendment) Rules,
                      updating the Indian Pharmacopoeia                   2005, were released 20 January 2005. Under the
                 • license approval as Central License Ap-                updated Rules, the Schedule Y was extensively
                      proving Authority for the manufacture               revised to bring the Indian regulations up to
                      of large volume parenterals, vaccines               par with internationally accepted definitions and
                      and biotechnology products and operat-              procedures.
                      ing blood banks and also of such other                   Schedule Y defines the requirements and
                      drugs as may be notified by the federal             guidelines for import and/or manufacture of
                      government from time to time                        new drugs for sale or for clinical trials. These


28 March 2007
harmonize with US and international standards
gulatory body in line with FDA...”
    include details of the application process and            US, UK, Switzerland, Australia, Canada, Germany,
    components of the application for permission to           South Africa or Japan. Permission is granted for
    conduct clinical trials, and the responsibilities of      these drugs, accepting the protocol approval of
    the sponsor, investigators, and the Independent           those countries. Category A application review and
    Ethics Committee (IEC). A clinical trial can only         approval are projected to take two to four weeks.
    be initiated after obtaining written permission           Category B clinical trial applications, however, are
    from DCG(I) and an IEC. A clinical trial application      reviewed under the previous system, by an expert
    utilizes Form 44, accompanied by documents                committee, which takes eight to 12 weeks for
    pertaining to chemical and pharmaceutical infor-          approval. This review time does not include poten-
    mation, animal pharmacology, toxicology data              tial delays due to incomplete applications and time
    and clinical pharmacology data. Other trial-related       required for sponsor responses to queries. Once an
    documents that must be submitted for approval             application is considered under Category B, it can-
    include the Investigator’s Brochure, trial protocol,      not be shifted to Category A, even if the applicant
    case report form, informed consent form, patient          produces an approval from a Category A country.
    information sheet and investigator’s undertaking.         For all applications, summarized information in
    Some additional requirements exist for studies            the Investigator’s Brochure, duly supported by
    in special populations, e.g., children, pregnant          an affidavit declaring the information furnished
    women, nursing women, elderly patients, patients          is based upon facts, may be acceptable in lieu of
    with renal or other organ system failure, and those       detailed pharmacology, toxicology and clinical
    on specific concomitant medication(s). In addition,       experience data. The DCG(I) also can request
    the trial’s regulatory status of the trial in other       guidance from such other independent govern-
    countries must be reported. The clinical protocol         ment agencies as the ICMR or Department of
    must be reviewed and approved by an IEC of, at            Biotechnology (for biotech products) on a case-by-
    minimum, seven members, including a medical               case basis, thus extending the review period.
    scientist, a clinician, a statistician, a legal expert,         Once written approval of the Schedule Y
    a social scientist and a common person from the           application is obtained from DCG(I) and an IEC,
    community. The Schedule Y application for per-            a clinical trial may be initiated. Products shipped
    mission to conduct a clinical trial must be accom-        from other countries require a separate import
    panied by a filing fee which is either Rupees (Rs)        license, called the T-License (Trial license), for
    50,000 (~$1200) for a phase I trial (called Human         investigational drug products. Once the license is
    Pharmacology Study); or Rs 25,000 (~$600) for             issued, it is valid for multiple shipments for one
    a phase II (Therapeutic Exploratory Study) or a           year. The T-License and Schedule Y applications
    phase III study (Therapeutic Confirmatory Study).         may be submitted together, so the license is issued
    Initial phase I studies can only be approved for          simultaneously with the application approval.
    drugs developed in India; however, repeat phase I         A separate application is required for shipping
    studies for other drugs can be approved.                  biological samples collected during the trial (e.g.,
          When a Schedule Y application is filed, the         body fluids) out of India. This application also
    office of the DCG(I) reviews it; the required review      can be submitted simultaneously with that for the
    period depends upon the trial’s regulatory status         clinical trial. Once the clinical study is approved by
    in other countries. To expedite the application           the DCG(I), the import license and No-Objection
    process and avoid detailed and prolonged review of        Certificate (NOC) for shipping biological samples
    information for studies already approved by certain       are granted within two to four weeks.
    countries’ regulatory agencies, on 22 November                  The protocol can be amended during the
    2006, the office of the DCG(I) issued the following       trial, as required. Protocol amendments fall into
    decisions. From 1 December 2006, all applications         three categories: (a) minor administrative and
    are divided into two categories: A and B. Category        logistical amendments that do not require any
    A includes clinical trials whose protocols have been      information or permission; (b) amendments that
    approved by EMEA or regulatory agencies in the            require DCG(I) to be informed but need not


                                                                                                                       RA focus 29
“One key element attracting pharmaceutical
companies to India is the lower clinical trial cost.”
                wait for permission, e.g., additional investigators,    foreign sponsor having no presence in India from
                amended Investigator’s Brochure or informed             independently requesting clinical trial approval.
                consent; and (c) those amendments requiring             This is easily circumvented by hiring one of the
                prior permission before implementation, e.g.,           rapidly growing number of local clinical research
                change in principal investigator, increase in subject   organizations (CROs) to be responsible for comply-
                numbers or major changes in study design, dose          ing with Indian regulations. Some global CROs also
                or treatment options. Type (a) and (b) amend-           have an Indian presence. While providing an attrac-
                ments should be communicated to the DCG(I)              tive opportunity for foreign sponsors to delegate
                and IEC within 30 days of implementation. All           their local regulatory responsibilities, selecting a
                unexpected serious adverse events (SAEs) must be        suitable Indian CRO is a critical step for off-shoring
                communicated to the DCG(I) and all participating        clinical development. Many Indian CROs have
                study investigators within 14 calendar days. SAE        personnel experienced in working on global clinical
                notification must be accompanied by proof that          trials for major pharmaceutical manufacturers in
                the same information has been submitted to the          both management and other levels. Almost all
                regulatory agencies in other countries where the        comply with ICH and FDA GCP guidelines. By
                study is being conducted. In addition, sponsors         incorporating some key elements into the CRO
                are required to submit progress reports on a            selection process, a sponsor can ensure quality
                format described in Schedule Y every six months.        clinical data. Items to review include:
                For studies prematurely discontinued for any            • personnel training records
                reason including lack of commercial interest in         • SOPs
                pursuing the new drug application, a summary            • QA documents
                report should be submitted within three months.         • previous investigators
                The summary report should provide a brief study         • clinical trial type
                description, the number of patients exposed to          • regulatory experience
                the drug, dose and duration of exposure, details
                of adverse drug reactions, if any, and the reason       Sponsors also should select an independent moni-
                for discontinuing the study or not pursuing the         toring company with a good reputation in conduct-
                new drug application. Schedule Y includes format        ing clinical trials in the relevant therapeutic area.
                and examples of all documents to be submitted
                to the DCG(I).                                          Timing the applications
                                                                        Since the Indian regulatory agencies require several
                Practical Issues of Conducting Clinical                 distinct applications, the sponsor needs to develop
                Trials in India                                         a clear regulatory strategy prior to initiating the
                Clinical data generated by Indian clinical sites        approval process. As noted previously, most of the
                have been used successfully for drug approval           applications can be filed simultaneously, thereby
                applications in the US, EU and other countries          saving considerable time. If the study is being
                over the last decade. However, India’s indigenous       reviewed and/or conducted in any countries desig-
                pharmaceutical industry still conducts only a small     nated Category A by CDSCO, it would wise to wait
                fraction of the total clinical trials in the country.   for at least one regulatory agency to approve the
                Most clinical studies in India are for foreign spon-    trial before filing with CDSCO to qualify for the
                sors. This raises some India-specific issues that a     faster approval time.
                sponsor with little of no physical presence in India
                should address.                                         Cost versus speed
                                                                        Another critical issue is the trial’s cost. One key
                Partner selection                                       element attracting pharmaceutical companies to
                Indian regulations require that foreign sponsors        India is the lower clinical trial cost. However,
                use a local agent as the lead contact for Schedule      such additional factors as the cost of obtaining
                Y and other application filings. This prevents a        Indian regulatory approval, additional quality


30 March 2007
assurance monitoring costs, etc, mean that the           cost. Some specific documents, e.g., the quality
direct savings may not be as large as expected for       of life questionnaire, might not have validated
smaller studies or those for rare indications. Cost      translations. Several organizations specializing
is a major advantage primarily in large studies with     in translation are available to help with this. All
more subjects. Faster subject recruitment remains        other study-related documents are in English and
a strong motivation even when the cost factor is         do not require translation. Some other issues,
not as attractive since it can bring cost benefits by    such as getting an unmarried female subject to
reducing the trial duration. Therefore, both cost        meet birth-control requirements for the study,
and expected subject recruitment rate should be          probably cannot be met and need to be addressed.
reviewed carefully when developing the Indian            Most such issues, however, can be addressed to the
component of a trial strategy.                           satisfaction of all regulatory agencies by IRB and
                                                         IEC reviews and approvals.
Investigator selection
Although India has many doctors, several hun-            Conclusion
dred hospitals and large pools of internationally        As its regulatory processes become more stream-
acclaimed scientific professionals, those numbers        lined, India is poised to take the lead in the global
do not directly translate into finding well-qualified    clinical development process. The country has a
and experienced clinical study investigators. India’s    strong reputation for meeting global professional
medical infrastructure is very different from that       parameters, as demonstrated by the information
in the US and EU; only 3-4% of patients carry            technology and service industries. The Indian
any form of health insurance, most paying for            government has a strong appreciation for pharma-
medical expenses out-of-pocket. As a result, there       ceutical sector growth and its regulatory agencies
could potentially be additional costs for meeting        are working closely with most international bodies
a subject’s standard of care. There is also an acute     to update the processes and smooth out kinks in
need to create increasing appreciation among the         the system. With more experience, the process will
Indian investigators of the benefits of participating    become more efficient and productive. India and
in clinical studies for both personal professional       the pharmaceutical services sector are working
development and patients. Another factor for             together to firmly position the country as a major
sponsors to consider is the actual expense of the        global player. Its easier regulatory hurdles and the
trials in Indian currency, to avoid any possibility of   fact that English is one of the primary languages
bias resulting from unreasonable financial benefits      give India a distinct advantage over China, other
to investigators or study personnel. The local CRO       countries in the region, and Eastern Europe.
should be able to assist the sponsor in establishing     Sponsors around the world would be a prudent
investigator compensation comparable to that in          to consider India as an important element in the
other countries.                                         drive to lower drug development costs. With the
                                                         proper strategy and partners, meaningful cost
Cultural issues                                          savings and quality data are possible.
In India, the personal physician strongly influences
patient decisions, as do family and friends, which       REFERENCE
could raise potential ethical issues with patient            C
                                                         1.	 	 linical	Trials	in	India	-	Industry	Report,	CYGNUS	Business	
                                                                   u
                                                             Cons	 lting	&	Research,	Nov	2005
recruitment. The Indian process leaves validating
IECs to the sponsor (and, by delegation, the part-       AUTHORS
ner CRO). It is up to them to assure that the IEC        Mukesh Kumar, PhD,	is	a	Senior	Regulatory	Affairs	Specialist	at	
meets membership requirements and utilizes the           Amarex	Clinical	Research,	LLC,	a	full-service	CRO	offering	complete	
                                                         trial	management	services	for	global	clinical	trials,	located	in	Ger-
processes (SOPs, minutes, etc.) necessary to pass        mantown,	MD,	USA.	Kumar	is	also	a	member	of	the	RAPS	Board	of	
an audit by Indian and/or international regulatory       Editors	for	Regulatory	Affairs	Focus.	
agencies. Most major medical centers are located         Surinder Kher, MD,	is	the	CEO	of	Clinsys,	Inc.,	a	CRO	managing	
in urban locations relatively well-educated patient      clinical	trials	in	India,	based	in	NOIDA,	India.		They	can	be	reached	
                                                         at	mukeshk@amarexcro.com	and	Surinder_Kher@clinsyscro.com	.	
populations. While English is the major language
of communication throughout India, the IECs
require that informed consent forms and all other
documents for subject review (e.g., study diary,
questionnaires) be translated into local languages.
This could mean translation into as many as 14
languages, with each translation adding to the


                                                                                                                                  RA focus 31

				
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