Biosimilar Regulation in India

A biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product is known as Biosimilar.

This could be the single fastest-growing biologics sector in the next five years – albeit from a small base – spurred by the convergence of major dynamics that will see new biosimilars enter the US market, bring additional molecules to Europe, and open up oncology and autoimmune disease areas to biosimilars for the first time ever. Biosimilars also bring clear potential for payers in the emerging pharmaceutical or “pharmerging” markets, such as Brazil, China and India. India have developed new regulatory guidelines for Biosimilar.

In New guideline DCGI has made mandatory the preclinical evaluation of biosimilar. The non-clinical studies should be comparative in nature and design to detect differences if any, between the similar biologics and innovator recombinant product. These should be conducted with the final formulation of the similar biologics intended for clinical use, unless otherwise justified. The non-clinical study design may vary depending upon the clinical parameters such as therapeutic index, the type and number of indications applied for etc. Assays like receptor binding studies or cell based assays (e.g. cell proliferation assays) should be conducted, when appropriate to establish comparability of biological activity. In cases where invitro assays do not reflect the pharamacodynamics, in-vivo studies should be performed. Comparative repeat dose toxicity with immunogenicity testing is also made compulsory in given route of administration, local tolerance should be evaluated.

According to new guideline, comparative Pharmacokinetic (PK) study on healthy subjects, Pharmacodynamics (PD) studies in most patients or healthy volunteers. If PD marker is available in healthy volunteers, PD in healthy volunteers can be done. Followed by a Phase III, Comparative safety and efficacy in relevant patient population is also mandatory for all biosimilar. However, in certain cases it can be waived. DCGI has also mandated the submission of PSUR 6 monthly for first 2 years and then annually for next 2 years, along with a Post Market study.

Regulatory applications and approvals issued at different stages of biosimilars product development

No.	Stage	Agency involved	Application	Approval
1	Manufacturing permission for test, analysis & examination	DCGI	Not Spesific	Permission (Manufacturing NOC)
2	Manufacturing License for test, analysis & examination	Local FDA	Form 30	Form 29
3	R & D	Institutional Biosafety Committee (IBSC)	Not Spesific	Permission (IBSC minutes)
4	Non-Clinical studies permission	RCGM	Form C3	Form C4
5	Submission of Non-clinical study report	RCGM	Form C5	Form C6
6	Clinical Trials	DCGI	Form 44	Permission (CT NOC)
7	Manufacturing License for CT batches	Local FDA (subject to CT NOC)	Form 30	Form 29
8	Manufacturing & Marketing permission	DCGI	Form 44	1. Form 45/46 (Finished product) 2. Form 46A (Bulk product)
9	Commercial Manufacturing License	Local FDA	Form 27 D	Form 28 D

Kind Regards,

Genelife Clinical Research- Ongoing Medical Device Clinical Trials

Genelife Clinical Research has started its first Medical Device Pilot Clinical Study for US FDA submission. Although we have participated in couple of US FDA studies in past but both were Pharmaceutical Clinical Trials. This is first time we are going to start a Medical Device Clinical Trials for Medical Device, within ENT therapeutic area. 

The study will be performed in a single site in India and we are hoping to recruit all patient volunteers in one month. The site selection procedure was dependent on not only the historic performance, type of Institute and its geographic location, paramedical staff, Investigator’s qualifications but we also considered the importance of patient referral. This we did considering the importance of project as well as the dependence of season on recruitment. 

Like our past studies we are hoping to complete this study before the time we proposed to our Sponsor. Hope we will achieve our target.

Kind Regards,

Advantages of eCase Report Form

No experiment is said to be complete until the results had been published or otherwise reported. It becomes even more important when the research directly involve human. Clinical research not only directly involves human subjects but can also affect human health if the reporting is not performed properly. And for proper reporting, proper data collection is very important.

In 70% clinical trials data collection is done manually through paper CRF in which Investigators manually record data on source documents and copy the same to the CRFs. Clinical monitors from CRO/sponsor verify the data and send the CRFs to CDM team. Paper CRF usually has an audit trail that is visible directly on the CRFs. Changes to individual fields are indicated with a single-line cross out, with the changed data appended along with the signature or initial of the person making the change, a date and perhaps a reason for change. Comments are written in the margin of these CRFs. Data clarification forms are appended to the CRF and contain the questions and responses that generated the change. This time honored format creates a complete case record with audit trail that is familiar to regulatory reviewers and investigators.

Though paper CRF gives an accurate, reliable and complete data, it is a laborious process and takes time for collecting CRF from investigational site, performing data entry and validation, and raising and resolving queries via Data Clarification Form (DCF). This has direct impact on time for drug to come in market. This suggested the idea of real time data management tools. Hence technology and innovation is used to its full extent and Electronic Data Capture (EDC) comes into limelight. The concepts for the design of electronic CRF are same as covered for paper.

EDC technology is expected to improve efficiency and accuracy of data, speed up decision making process and reduce cost. It resulted in a reduction of paper consumption and load on clinical monitors to manage such huge volume of paper. This paradigm has reduced the risk of damage of CRF during transit. It is due to these reasons EDC is preferred to traditional method.

GCP and 21 CFR Part 11 require validation for a software system used for processing clinical data. System validation includes user requirement specifications, functional specification, design specifications, implementation and testing. 21 CFR Part 11 defines the criteria under which electronic records and electronic signatures are considered to be trustworthy, reliable and equivalent to paper records. Part 11 has requirements to implement controls including audits, system validations, audit trails, electronic signature and documentation for software and systems involved in processing electronic data that are a) required to be maintained by FDA rules and b) demonstrate compliance to a predicted rule.

In electronic CRF, investigator enters data and signs electronically for accuracy, reliability and completion of all data points. It assembles data from multiple tables into a single Web page. However, the investigator later can add, modify or delete data in the EDC system in future at any time-point, until the electronic CRF are locked and no more updating is permitted. Investigator at this point should sign for the changes made to electronic CRF data points which were entered or changed. At the end, Investigator has to sign for all data entries, modifications or deletions as he is owner of that clinical data. This is why signing by the investigator is so important in electronic data capture.


Audit trails and comments are not found in the margins of an eCRF- they are viewable through links from the CRF and also are simply user-friendly representations of data tables. Electronic CRF is not just a repository but is designed to allow the backend systems to perform efficiently. The forms have built in edit checks and no longer accept entered data. POPs will appear if there is any error in entry/incorrect value. Query management can be done within minutes as opposite to paper CRF. Queries can be managed through computer user interface rather than paper based clinical trial. We can raise query directly on website and monitor can log on the query message and provide his resolutions there. Since high quality data are available at the time of data entry by the study site, biostatistician can review and analyze very early. As a result almost all statistical programs are completed before the visit of last patient.

Roles of data management staffs that have changed with the arrival of eCRF:

1. Data entry task shifted to site personnel/investigator 
2. Data review/cleaning became a joint venture of site personnel/investigator, clinical monitor and CDM team 
3. Trainer is needed in CDM to impact training functionality of EDC software 
4. Clinical monitors to perform source data verification which is a QC task, 
5. CDM members have to generate extra manual review listings and perform this task manually 
6. Clinical monitors or data management team to address/resolve technical issues faced by site personnel/investigators. 

However few challenges exist and researchers are trying to evaluate if quality of data produced by traditional paper based studies is better or equivalent compared to data generated by EDC. Investigational site personnel find data entry as a tedious task. Multiple EDC software has created confusion to non-CDM members. There is a need to develop effective training for EDC software, which is study specific for a given protocol. Hence investigational sites require technical support and guidance. One of the most common deficiencies cited by the FDA is the lack of documentation since the original observations are entered directly into a computer system; in this case electronic record becomes the source document. Paper is eliminated but EDC uses technologies like internet, software EDC and other additional services such as call center, so it cannot be considered as a cost-effective solution.

There is no doubt that electronic data capture is the future as it increases the speed of data processing and assures high quality data with lower error than paper CRF of Clinical Research. However, deployment of these advances should be implemented carefully as it requires consideration of desired outcome and the needs of people involved in the process.

Representing

Genelife Clinical Research - Clinical Data Management Department

Patient Recruitment and Retention- Genelife Approach

With recent times INDIA is booming as developing place for all the fields along with Clinical Research. Because of the large population and diversity India is one of the hot spot for clinical research at the global frontier. The population across country understanding the real health care need and the importance of drug discovery where the critical link is Clinical Research.

Clinical Development is the key milestone for a drug to get into the market shelf. Clinical Studies got vital role for better understanding of the discovered molecule activity in human and the subjects who are intended consumers of the drug.

For a successful drug launch the Clinical Studies and population participation is a demanding process which should happen for achieving the objectives of the drug utility and to provide best health care to save lives.

The connectivity of process and the prominent points of patient recruitment and retention;

·  Clinical development phase initiation                           

·  Clinical Trials protocols development

·  Therapeutic Indications understanding

·  Patient availability & assessments

·  Patient recruitment and retention strategies

Patients Availability and Assessments – The study design and the indications were the base to engage and assess the patients availability and assessments must be done on the basis of:

o   Ethnicity

o   Demographics

o   Geographic

o   Behavioral

o   Psychographic

o   Incidence and Prevalence

o   Epidemiology

Advertising programs brings attention about the research happening and ignites intentions for connecting population to participate in the research. The healthier and understandable advertising with proper methodologies really brings branding for the drug as well. Across globe the concept of medical research and the potential risks and benefits has to be socially publicized through media by having regulatory intimacy.

The consistent advancements through ethical research for establishing bliss for humanity through medicines and participated population and the benefits received by them by value and appreciation must be taken forward into society and public by media. These kinds of steps will enhance awareness across communities for contributing into research and development.

Patient retention throughout the study is the most important task and it can be achieved by the classic methodologies and the intimacy of Investigator and site team plays vital role to achieve maximum retention rate.

Patient retention is possible with; GENELIFE CLINICAL RESEARCH methodology

·      Simple explanation of the study and the milestones of it

·      Clear and complete understanding about the patient importance and expectation from them

·       Explaining the potential benefits risks and facts about the study and their role with intimacy in terms of health, reimbursements (travel & meal) and making patient comfortable at clinic

·     Whom to contact if patient is having any questions or concerns and being available at any time accessible for patients.

·        Make patient clear about quit procedures and its implications and results.

·        Make them feel appreciated and valued as they were critical contributors for the research

·        Consistent interaction with patients and follow up.

Patient recruitment is possible with; GENELIFE CLINICAL RESEARCH methodology.

Focus groups- the population eligible for study participation. Identifying focus groups and finding the communities through available data resources.

·     Communicating and engaging different critical disease communities across the globe by accessing the GP’s and various organization and independent disease surveys making GENELIFE CLINICAL RESEARCH potential with subject availability.

·      The DSR – Disease Surveillance Reports across different horizons with floating life standards and various conditions based survey is making GENELIFE CLINICAL RESEARCH understand the proximities of disease prevalence.

·     Building extensive relationships with research organizations, institutions, academic labs, hospitals, clinics and medical fraternity with ethical research oriented intention is paving way to access patient pool for desires indications across therapeutic indications.

These steps improving the Clinical research employing potential, to move on with best patient recruitment and retention strategies for accomplishing the study primitives.

GENELIFE CLINICAL RESEARCH employs such methodologies with global outreach to provide compendious clinical development solutions      

Regards,

GENELIFE CLINICAL RESEARCH

Project Management Approach

Genelife Clinical Research is among one of the few CRO’s who have adopted Project Management Approach. This model widely helps us conserve timeline and cost. This model is predominantly devised from and for complex studies like cancer, cardiology clinical trials, but it can be retrofitted to other therapeutic areas. The basis of this model is the disease surveillance study which we conducted across India to study the trends of diseases.

Clinical Research industry demands quality data in most cost effective manner, we have designed Genelife Model. Industry trends and patterns have changed due to economic slowdown which suggests cost effective research and CRO can be best partner to achieve the same. 

In this model we have taken the Clinical Research process as a system and we identify exact input with well-defined process to bring effective output. The first input comes from Study Feasibility Analysis (SFA) Site Feasibility analysis (SFA); due to available disease prevalence data this process has become very fast and cost effective for us. This procedure is conducted on the basis of initial Project Plan (PP).

Study & Site Feasibility Analysis (SFA): Genelife Clinical Research has feasibility which works under Project Management Team. This team understands the objectives of the study and provides the solution to main question of project like what to be done; how to be done; at what cost; in what time. During site feasibility we emphasize on site not only with high disease prevalence but also with clinical research supportive environment. Clinical Research supportive environment is very important aspect for physician referral and it is not considered most of the time. 

Project Planning (PP): in our model we have divided Project planning in two major parts. In 1st is for initial phase is for training and performing initial activity like feasibility. After receiving the feasibility reports we develop plans like risk management plan, communication plan, QA plan, safety plan, monitoring plan, Data management Plan, SAP plan etc for stating how to complete a project within a certain timeframe, usually with defined stages, and with designated resources. In totality the plan will include setting quantitative objectives, identifying deliverables, identify & manage foreseen and unforeseen risk, overcome bottleneck planning the schedule and making supporting plans.

Project Management & Commencing: Once a project moves into the Execution Phase, the project team and the necessary resources to carry out the project should be in place and ready to perform project activities. The project team handover the activities to different departments and start analyzing the progress of work. 

Last stage of this model is suitable output which is directly dependent on above two steps. As per Genelife Model, with precise inputs and efficient process, one tends to get desired output in terms of faster regulatory approval, quality data, shorter timelines and better return on investment.

Representing

Genelife Clinical Research – Project Management Department

The Challenges with Drug/Device Combination Products

Active medical devices are that device which interact with the body systems and is has been highly effective. Drug is a common active component of medical devices such as inhalations sprays, nebulizers, stents, some orthopedic implants etc. . When the devices are merging, there is always a look to how two industries can merge at least for common interest areas to have compact medical package. Although the concept primarily looks to be invaded by issues, still situation is practically manageable. Several large companies in other business segments and a few hospitals manage several disciplines already.

For this, we need to collate some factoids for comprehensive evaluation of the situation. As the interrogator has correctly put the three areas to bear the primary stress will be regulatory, engineering and Quality. One functional sect area that would bear a lot of stress will be training. The segments those will be eased by this merger will be clinical, marketing and finance. The functionality of merger is integral in most segments other than production. There can be two scenarios about production facility: First, production of Drugs and devices in the same facility, and Second, Production of Drugs and Devices in two distinct facilities. The second case looks to be more feasible model for regulatory and engineering reasons. There can be two units in one premise, but intersecting utility is practically less possible for execution.

The first and the major impact will be on the regulatory and QMS professionals who need to manage compliances for highly diverse set of regulation in one infrastructure. The first scenario is when there is complete merger including production units. Let us discuss the compliance factoids of Audits in both cases. Good Manufacturing practice applies to both, Medical Devices as well as Drugs, with some fine tuning required. In This case, meeting systemic requirements of ISO 9001 and to an extent GMP will be relatively easy. Contrarily, it would critically elevate challenge in compliances for ISO 13485 and US FDA CRF section 510k. Some parts of medical devices will interfere with drugs production and vice versa. Storage, recycling and disposal needs; water, ground clearance, environmental needs, Infrastructure and machinery needs are three sets of diverse requirements. Compliances of these three sets are commonly seen to be antagonists to each other and hence is an edge-walk for Quality managers. The Regulators would face several constrains in Audits and inspections for intersecting facility. When the facility is intersecting, for all practical reasons they need to operate as two different units. Otherwise, they will keep complicating each other’s regulatory requirements.

Similar load will be taken by engineers, responsible for maintenance of infrastructure and machinery. Medical devices require sterilization of the products and drugs do not. Some byproducts of medical devices such as ETO fumes are known to have adverse effects on composition of pharmaceutical agents, and a few raw materials of pharmaceutical agents may have corrosive or other chemical impacts on raw material or finished goods of medical devices. The Engineering section has to develop efficiency in handling the diversity and counterproductive nature of some components in merging systems. Requirements of Maintenance in terms of Air Hosing units, Backups, machinery etc. will rage very wide.

With the merger of production and other facility of medical device and drugs, certain unforeseen manageable issues may pop up as the progress in fields is seen, yet it will be highly optimistic step up in reducing healthcare cost and deliver even better quality. Costs of regulatory set up, human resources, clinical, Engineering, benchmarking, preclinical and quality check testing etc. will significantly reduce. Marketing strategies like product bundling, in-house production of active components like drugs, polymers and merging of logistics, transportation, storage and corporate requisites will help availing quality products in minimum costs. When weighing Risks and challenges vs. benefits the the homeostatis shifts towards the merger.

Dr. Ashish Indani

Head, Clinical Operations

GENELIFE CLINICAL RESEARCH

29/243, Unnat Nagar II,

Off SV Road, Goregaon (W)

Mumbai 400063

Maharashtra, INDIA
Email: ashishi@genelifecr.com

Under The Scanner : Medical Device Trials

Our Managing Director, Dhirendra V. Singh has featured in the march, 2012 edition of Express Pharma, which is entitled "Under The Scanner : Medical Device Trials,", please find the link below:

http://www.expresspharmaonline.com/20120331/market01.shtml 

Though this article is written by someone else, but we believe that this article provides clear picture of Indian Regulation related to medical device. 

Genelife Clinical Research IInd Anniversary Celebration

Genelife Clinical Research has successfully completed second year with all the enthusiasm of work, challenges and fun that was put together and served in the field of clinical research. At this propitious occasion I would like to share the progress and furtherance of Genelife Clinical Research. As on 26th February bookmarked in our diaries permanently I would like to thank every helping hand that has made Genelife Clinical Research to be what she is now. 

The year started with the farewell of one of the partner of Genelife and we are planning to end this financial year as Private limited company.

After initial hiccup the year started with an Oncology Clinical Trials followed by a Asthma Clinical trials. Ad hoc, we have two new oncology studies, two medical device studies that are ameliorating and an all-encompassing presence globally. Also there are five studies which are waiting to be board. 

Genelife has also augmented its reach within therapeutic areas and developed a good rapport with the investigators and clients that we have come across in any projects at hand. Though even there are some minor mistakes that may have happened, but it is said that "a mistake is simply another way of doing things" so we improve and move on to correcting them and bettering the quality of work. Genelife Clinical Research has continued to identify and screen fresh sites and potential investigators in any kind of upcoming studies as we believe in keeping an open mind and a compassionate heart.

In order to upgrade the system to be “the most respected CRO” Genelife Clinical Research has introduced Data Management System with a well-qualified staff. We have also changed the location of Genelife from Thane to Mumbai (Goregaon). The working space of the new office is more which is essential for us to serve the needs of Clinical Research with the number of growing projects.

On international front also Genelife Clinical Research has shown her presence. We are waiting to take 3 TGA (Australian Regulatory Body) projects on board and planning to start a Russian medical devise project. Also in concert with the GCC government authorities our company has been exposed to the new elements of research industry. Apart from this Genelife Clinical Research has also identified the location at places like the United States and Germany in order to expand our operations in North America and Europe.

This all is possible because of our client, support and well-wisher and we would like to thank & show heartiest gratitude towards our clients and well-wishers for all the support and stand provided till date and surely time ahead.

"And no we don’t know where it will lead; we just know there's something much bigger than any of us"

"Each year has been so robust with problems and successes and learning experiences and human experiences that a year is a lifetime here... so this has been two lifetimes for us...”

Regards

GENELIFE CLINICAL RESEARCH

Email: info@genelifecr.com


Website: http://www.genelifecr.com/ Blog: www.genelifecr.blogspot.com

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GENELIFE CLINICAL RESEARCH: STEPPING TO NUTRACEUTICALS

After a prompt start in conducting a clinical trial for DCGI submission on a therapeutic area of Asthma, Genelife Clinical Research is all set to start a trial of Nutraceuticals on Breast Cancer. The term

"Nutraceuticals" may require a brief introduction. Nutraceutical is a word introduced by US FDA for possibly a pormanteu of "Nutritional" and "pharmaceuticals". Health Canada defines the term as, "A Nutraceutical is a product isolated or purified from of foods or food like material that is generally sold in medicinal forms not usually associated with food. A Nutraceutical is demonstrated to have a physiological benefit or provide protection against chronic disease. These may range from isolated nutrients, dietary supplements and specific diets to genetically engineered foods, herbal products, and processed foods such as cereals, soups, and beverages." In a nutshell, Nutraceuticals are Natural Adjuvant having affirmative medical and health benefits; including the prophylaxis of disease, maintenance of nutrition and basic health profile and restitution of cumulative aftereffects of treatments received. Major Indications also include facilitation of desirable therapeutic outcomes of concomitant therapeutic agents. All these indications are for improving quality of life in subjects who are healthy or dependent upon long-term medication and has met with great monetary success.

Genelife is reaching out with nutraceutics to the world’s third most common cause of mortality, the Cancer. In this condition Morbid and uncontrolled division of cells and their invasion into other tissues lead to formation of malignant tumors and cause impediment to the life process”. Breast cancer being one of the most common types of cancer, is taken a basis for this study. Planned typical treatment of Breast Cancer, just like most others, includes surgery, radiation therapy, chemotherapy either singular or in combination. With the evolvement of radiation therapy or chemotherapy, the Life expectancy, five years survival rate, retardation of disease process is achieved. Unfortunately, the therapy; due to its side effects; has significant deterioration in the quality of life. To overcome this, Ocimum has developed a herbal Nutraceutical product and successfully tested it in animals. This formulation is a plant extract expected to reduce cumulative after-effects and side-effects of treatments of cancer and also helps in improvising in the quality of life. REFORM 1 ca is a randomized single-center, placebo controlled, study for safety and efficacy outcomes of one of this herbal adjuvant in a close small cohort. As a Strategy of study, the subjects will continue with prescribed treatment such as chemotherapy or radiotherapy. This study is powered and designed to achieve the outcome listed down:

• Improving the quality of life

• Reducing the side effects of chemotherapy / radiation therapy given as a treatment of Breast Cancer

Innovative study design as a "Genelife factor" has made the study interesting and adorable. The outcomes of the study are looked forward to introduce new heights to all Nutraceutical industry and hopefully sooth sufferings of Cancer patients.

Thanks & Regards,

 GENELIFE CLINICAL RESEARCH