UNIT VIII

Latest developments in ICH

EMEA: Enhancement of International activities

• EMEA Roadmap: Enhancement of International activity to  better protect public health, facilitate access to medicines and stimulate innovation

• EC-EMEA Bilateral relationships: Confidentiality arrangements with USA (2003), Japan (2007), Canada (2007)

• Mutlinational relatioships: ICH remains the key forum for  harmonisation of human pharmaceuticals. ICH is an important  technical basis for our international collaboration success

Over 50 ICH Guidelines  finalised, new, under revision

• Efficacy

 - 14 topics/17 guidelines

• Safety

 - 8 topics/16 guidelines

• Quality

 - 9 topics/23 guidelines

• Medical Dictionary

 - MedDRA

• Electronic Standards

 - eCTD, ESTRI, E2B,

• Common Technical Document- CTD

Guidelines extend over entire product life cycle

(ref:http://www.emea.europa.eu/docs/en_GB/document_library/Presentation/2009/11/WC500010482.pdf)

Purpose

The purpose of ICH is to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines by recommending ways to achieve greater harmonisation in the interpretation and application of technical guidelines and requirements for product registration. Harmonisation would lead to a more economical use of human, animal and material resources, and the elimination of unnecessary delay in the global development and availability of new medicines while maintaining safeguards on quality, safety, and efficacy, and regulatory obligations to protect public health.

ICH guidelines have been adopted as law in several countries, but are only used as guidance for the U.S. Food and Drug Administration.

Structure

The ICH has four major parts:

ICH Steering Committee,

ICH Coordinators,

ICH Secretariat and

ICH Working Groups.

The Steering Committee, made of six ICH Parties, governs the ICH, determining the policies and procedures, selecting topics for harmonisation and monitoring progress of harmonisation initiatives. The ICH consists of:

European Commission,

European Federation of Pharmaceutical Industries and Associations (EFPIA)

Ministry of Health, Labour and Welfare (Japan)

Japan Pharmaceutical Manufacturers Association (JPMA)

Food and Drug Administration (FDA)

Pharmaceutical Research and Manufacturers of America (PhRMA)

The ICH Coordinators represents each ICH Party to the ICH Secretariat on a day-to-day basis.

The ICH Secretariat is primarily concerned with preparations for, and documentation of, meetings of the Steering Committee as well as coordination of preparations for Working Group (EWG, IWG, Informal WG) and Discussion Group meetings.

The ICH Working Groups are created by the Steering Committee when a new topic is accepted for harmonisation, and is charged with developing a harmonised guideline that meets the objectives outlined in the Concept Paper and Business Plan.

(Ref: http://www.ich.org/about/faqs/article/how-is-ich-structured.html)

Implications

In the field of drug efficacy and safety ICH has produced 26 guidelines describing technical requirements related to the process of registration of new chemical entities and products obtained by biotechnology. As already mentioned, the scientific level of each guideline is high and reflects state-of-the-art technology.

Although intended primarily for ICH countries, guidelines related to drug safety and efficacy may also be of use to non-ICH countries to create awareness of the subject, and for reference and guidance purposes for national drug regulatory authorities when producing national legislation. They may also be used for education and training purposes. This applies particularly to ICH guidelines in the safety area (guidelines S1A to ICH S7, especially those on carcinogenicity and genotoxicity). It should be stressed that the majority of ICH guidelines in the areas of safety and efficacy deal with topics for which no documents of a regulatory nature previously existed, which considerably to their usefulness.

It should be recognized that WHO has produced only a limited number of materials on topics concerned with safety and efficacy. They relate to good clinical practice (GCP), for which WHO has produced guidelines, and to reporting of adverse drug reactions, for which WHO maintains its Centre for International Drug Monitoring in Uppsala, Sweden. As the WHO GCP guidelines are now in the process of revision, it is intended that the revised version should indicate the material contained in ICH's guideline.

Attempts to apply some ICH guidelines related to drug safety and efficacy in practice in non-ICH countries can give rise to considerable difficulties, especially when full implementation is attempted in countries that lack adequate resources. Specific examples of such difficulties are presented below.

ICH guideline E5, "Ethnic factors in the acceptability of foreign clinical data", recommends a framework for evaluating the impact of ethnic factors on the effect of the medical product. Some commentators claim that the guideline may limit the scope of decision of national regulatory authorities as to the need for clinical studies to be conducted in the country. This may create problems with the verification of the actual efficacy of drugs in local situations, and may also create obstacles for local pharmaceutical development. At the same time, the need for local clinical trials must be scientifically justified.

ICH guideline E2C "Clinical safety data management: periodic safety update reports (PSUR) for marketed drugs", which lays down a format and content for comprehensive periodic safety updates and recommends a six-monthly periodicity for such update reports, is highly resource-intensive. The resources required to maintain the system are beyond the means of most non-ICH countries. It may be considered that non-ICH countries would benefit more from a digest of work done by the ICH drug regulatory authorities on each individual product, provided such digests are produced and suitably disseminated.

The ICH GCP guideline (E6, "Good Clinical Practice: consolidated guideline") deals with the planning, conduct, monitoring and reporting of clinical trials. Its object is to facilitate the mutual acceptance of clinical trial data in ICH countries. However, WHO's constituency includes all the world's cultures. The purpose of the WHO GCP guidelines is to provide globally applicable guidance for the conduct of clinical trials, thereby assuring the ethical and scientific integrity of research.

The ICH GCP guidelines are used by non-ICH countries to develop their own GCP guidelines. They are more detailed and user-friendly than current WHO GCP guidelines, but they do not address country-specific issues. The conduct of clinical trials should be linked to scientific justification. There is a need for WHO to revise its current guidelines taking these factors into account. The WHO GCP guidelines are currently being revised to adopt a modular approach that will enhance their educational value.

ICH guideline M3, "The timing of non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals", is important for regulatory authorities that control and assess product development prior to drug product approval. It also provides the pharmaceutical industry with guidance on the approach that should be taken to perform various tests prior to submission of evidence to regulatory authorities. It would be useful to non-ICH countries for better awareness and understanding of requirements so that they could establish national approval requirements appropriate to their situation.

ICH guideline M1, "Medical terminology" (including Medical Dictionary for Regulatory Activities Terminology, MedDRA Terminology), was developed as a medical terminology covering all aspects of drug regulation ranging from authorization to post-marketing surveillance. It contains terms for adverse drug reactions (ADRs) and also for diseases, investigations and patient history. It includes terms from the WHO Adverse Reaction Terminology (WHO-ART) and ICD-9, but uses a different structure and many more terms. The advantages of using MedDRA have been stated as specificity for data entry, flexibility for data retrieval, and standardization for international communication. However, there are significant problems in the use of MedDRA by non-ICH countries, particularly difficulties in installing and using the terminology and its cost. Recommendations by WHO to ICH to retain WHO-ART as a pharmacovigilance subset of MedDRA and to involve WHO in the review of MedDRA were not considered by ICH to be workable. ICH's position has forced WHO to continue with the further development of WHO-ART. The relationship of WHO-ART with ICD-9 and 10 also has important public health and epidemiology aspects. There is no satisfactory proposal from ICH to address these points.

A new ICH initiative to develop activities in the area of post-marketing surveillance was proposed at the Fifth International Conference on Harmonization (November 2000). Three topics were suggested in the first instance:

(1) periodic safety update information;

(2) safe roll-out of new drug products;

(3) case reporting.

(Ref : http://apps.who.int/medicinedocs/en/d/Jh2993e/7.html)

Guidance notes

The ICH topics are divided into four categories and ICH topic codes are assigned according to these categories.

1.       Quality Guidelines

Harmonisation achievements in the Quality area include pivotal milestones such as the conduct of stability studies, defining relevant thresholds for impurities testing and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP) risk management.

Stability Q1A - Q1F

Analytical Validation Q2

Impurities Q3A - Q3D

Pharmacopoeias Q4 - Q4B

Quality of Biotechnological Products Q5A - Q5E

Specifications Q6A- Q6B

Good Manufacturing Practice Q7

Pharmaceutical Development Q8

Quality Risk Management Q9

Pharmaceutical Quality System Q10

Development and Manufacture of Drug Substances Q11

Cross-cutting Topics

2.       Safety Guidelines

ICH has produced a comprehensive set of safety Guidelines to uncover potential risks like . testing strategy for assessing the QT interval prolongation liability: the single most important cause of drug withdrawals in recent years.

Zip file with all ICH Safety Guidelines in Word format

Carcinogenicity Studies S1A - S1C

Genotoxicity Studies S2

Toxicokinetics and Pharmacokinetics S3A - S3B

Toxicity Testing S4

Reproductive Toxicology S5

Biotechnological Products S6

Pharmacology Studies S7A - S7B

Immunotoxicology Studies S8

Nonclinical Evaluation for Anticancer Pharmaceuticals S9

Photosafety Evaluation S10

Cross-cutting Topics

3.      Efficacy Guidelines

The work carried out by ICH under the Efficacy heading is concerned with the design, conduct, safety and reporting of clinical trials.  It also covers novel types of medicines derived from biotechnological processes and the use of pharmacogenetics/ pharmacogenomics techniques to produce better targeted medicines.

Zip file with all Efficacy Guidelines in Word format

Clinical Safety E1 - E2F

Clinical Study Reports E3

Dose-Response Studies E4

Ethnic Factors E5

Good Clinical Practice E6

Clinical Trials E7 - E11

Clinical Evaluation by Therapeutic Category E12

Clinical Evaluation E14

Pharmacogenomics E15 - E16

Cross-cutting Topics

4.      Multidisciplinary Guidelines

Those are the cross-cutting topics which do not fit uniquely into one of the Quality, Safety and Efficacy categories.  It includes the ICH medical terminology (MedDRA), the Common Technical Document (CTD) and the development of Electronic Standards for the Transfer of Regulatory Information (ESTRI).

Zip file with all Multidisciplinary Guidelines in Word format

MedDRA Terminology M1

Electronic Standards M2

Nonclinical Safety Studies M3

Common Technical Document M4

Data Elements and Standards for Drug Dictionaries M5

Gene Therapy M6

Genotoxic Impurities M7

Electronic Common Technical Document (eCTD) M8

(Ref:   http://www.ich.org/products)

Inspections INDIAN / USA / EU Ethics approval system 

INDIAN

Regulatory inspections are important to evaluate the integrity of the data submitted to health authorities (HAs), protect patient safety, and assess adequacy of site/sponsor quality systems to achieve the same. Inspections generally occur after submission of data for marketing approval of an investigational drug. In recent years, there has been a significant increase in number of inspections by different HAs, including in India. The assessors/inspectors generally do a thorough review of site data before inspections. All aspects of ICH-GCP, site infrastructure, and quality control systems are assessed during the inspection. Findings are discussed during the close out meeting and a detailed inspection report issued afterward, which has to be responded to within 15–30 days with effective Corrective and Preventive Action Plan (CAPA). Protocol noncompliance, inadequate/inaccurate records, inadequate drug accountability, informed consent issues, and adverse event reporting were some of the most common findings observed during recent Food and Drug Administration (FDA) inspections. Drug development is being increasingly globalized and an increased number of patients enrolled in studies submitted as part of applications come from all over the world including India. Because of the steep increase in research activity in the country, inexperienced sites, and more stakeholders, increased efforts will be required to ensure continuous quality and compliance. HAs have also made clear that enforcement will be increased and be swift, aggressive, and effective.

Regulatory inspections are an important and essential part of clinical research to evaluate the integrity of the data submitted to health authorities (HAs), presence of infrastructure to conduct clinical research, measures implemented to protect patient’s interest and safety, adequacy of site/sponsor quality systems, and verification of compliance with the principles of ICH-GCP as well as local regulations.

Inspections generally occur after submission of data for marketing approval of an investigational drug; however, inspections may happen at any time during the conduct of the trial like FDA’s Early Intervention Program.

All HAs like US FDA, EMA (European Medicines Agency) and others to whom data have been submitted from Indian site(s) may conduct inspections at the respective study sites.

Drug Controller General India (DCGI) has jurisdiction to inspect all clinical trials. DCGI has conducted inspections to investigate issues, where required. A routine inspection program will also start in near future.

A closer look at recent inspection frequency figures suggests a significant number of inspections occurring outside the US including in the Asia Pacific region. In fiscal year 2009, FDA Center for Drug Evaluation Research (CDER) clinical investigator inspections totaled 458 and 119 of those (26%) were outside the US. The FDA Clinical Investigator Inspection List (CLIL) website, an online posting of inspections with final classifications, shows 78 investigator site inspections in the Asia-Pac region, out of which 14 (6 in 2009) have been in India.

The results have been positive with either “No Action Indicated” or “Voluntary action Indicated.” The findings were in categories of Drug Accountability, Protocol Compliance, Inaccurate Records, and Failure to follow Investigational Plan.

Because of the steep increase in research activity, inexperienced sites, and more stakeholders, a lot of effort will be required to ensure continuous quality and compliance to maintain this positive trend in inspection outcomes.

EMA has also increased inspections in the region with India being one of the most inspected countries (eight inspections between 1997 and 2008) outside the EU (European Union). This is in keeping with the increased number of subjects recruited from the region (11.6% in pivotal studies submitted in 2007 versus 4% for submissions between 2005 and 2007) for the pivotal studies submitted to EMA for approval

(Ref : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3043366/)

USA

This guidance is intended to provide information about FDA inspections of clinical investigators

conducted under FDA’s Bioresearch Monitoring (BIMO) Program. This document supersedes

FDA’s Information Sheet Guidance, "FDA Inspections of Clinical Investigators," dated January

2006. This document has been revised to provide updated information and is being issued in

accordance with the agency’s regulations on Good Guidance Practices (21 CFR 10.115).

FDA's guidance documents, including this guidance, do not establish legally enforceable

responsibilities. Instead, guidances describe the agency's current thinking on a topic and should

be viewed only as recommendations, unless specific regulatory or statutory requirements are

cited. The use of the word should in agency guidances means that something is suggested or

recommended, but not required.

FDA developed its BIMO Program to help ensure the protection of the rights, safety, and welfare

of human research subjects involved in FDA-regulated clinical trials, to verify the accuracy and

reliability of clinical trial data submitted to FDA in support of research or marketing applications, and to assess compliance with statutory requirements and FDA's regulations  governing the conduct of clinical trials. Among other activities, the FDA BIMO Program

involves site visits to clinical investigators, sponsors, monitors, contract research organizations,

Institutional Review Boards (IRBs), nonclinical (animal) laboratories, and bioequivalence

analytical laboratories. This document addresses site visits to clinical investigators who conduct

clinical investigations that are regulated by FDA under 21 USC 355(i) or 21 USC 360j(g).

WHEN ARE CLINICAL INVESTIGATOR INSPECTIONS CONDUCTED?

FDA conducts clinical investigator inspections to determine if the clinical investigators are

conducting clinical studies in compliance with applicable statutory and regulatory requirements.

Clinical investigators who conduct FDA-regulated clinical investigations are required to permit

FDA investigators to access, copy, and verify any records or reports made by the clinical

investigator with regard to, among other records, the disposition of the investigational product

and subjects’ case histories. See 21 CFR 312.68 and 812.145. The FDA investigator typically

performs this oversight function through on-site inspections designed to document how the study

was actually conducted at the clinical investigator’s site. For investigational drug studies,

clinical investigators must retain study records for a period of two years following the date a

marketing application is approved for the drug for the indication for which it is being

investigated; or, if no application is to be filed or if the application is not approved for such

indication, until two years after the investigation is discontinued and FDA is notified. See 21

CFR 312.62(c). For investigational device studies, clinical investigators must retain study

records for a period of two years after the latter of the following two dates: The date on which

the investigation is terminated or completed, or the date that the records are no longer required

for purposes of supporting a premarket approval application or a notice of completion of a

product development protocol. See 21 CFR 812.140(d).

FDA conducts both announced and unannounced inspections of clinical investigator sites,

typically under the following circumstances:

• to verify the accuracy and reliability of data that has been submitted to the agency;

• as a result of a complaint to the agency about the conduct of the study at a particular

investigational site;

• in response to sponsor concerns;

• upon termination of the clinical site;

• during ongoing clinical trials to provide real-time assessment of the investigator’s

conduct of the trial and protection of human subjects;

• at the request of an FDA review division; and

• related to certain classes of investigational products that FDA has identified as products

of special interest in its current work plan (i.e., targeted inspections based on current

public health concerns).

HOW ARE CLINICAL INVESTIGATOR INSPECTIONS CONDUCTED?

Upon arrival at the clinical investigator study site, the FDA investigator will display his/her FDA

credentials and issue a completed Form FDA 482 (Notice of Inspection) to the clinical

investigator or appropriate study staff. FDA is authorized at reasonable times to access, inspect,

and copy any required records related to the clinical investigation. See section 704 of the

Federal Food, Drug, and Cosmetic Act (21 USC 374), 21 CFR 312.68, and 21 CFR 812.145.

During an inspection at the site of a clinical investigator, the FDA investigator typically verifies

compliance with the regulations governing the use of investigational products and human subject

protections at 21 CFR parts 50, 56, 312, and/or 812, by inspecting records and talking to

individuals involved in the conduct of the study to ascertain:

• who performed various aspects of the protocol for the study (e.g., who verified inclusion

and exclusion criteria, who obtained informed consent, who collected adverse event

data);

• whether the IRB approved the protocol, informed consent form, and any amendments to

the protocol prior to implementation;

• whether the clinical investigator and study staff adhered to the sponsor’s protocol and

investigational plan and whether protocol deviations were documented and reported

appropriately;

• whether informed consent documents were signed by the subject or the subjects’ legallyauthorized representative prior to entry in the study (i.e., performance of any studyrelated procedures);

• whether authority to conduct aspects of the study was delegated, and if so, how the

conduct of the study was supervised by the clinical investigator2;

• where specific aspects of the investigation were performed;

• how the study data were obtained and where the study data were recorded;

• accountability for the investigational product, including shipping records and disposition

of unused investigational product;

• whether the clinical investigator disclosed information regarding his financial interests to

the sponsor and/or interests of any subinvestigator(s), spouse(s) and dependent children3;

• the monitor’s communications with the clinical investigator;

• the monitor’s evaluations of the progress of the investigation; and

• corrective actions in response to previous FDA inspections, if any, and regulatory

correspondence or sponsor and/or monitor correspondence.

The FDA investigator also may audit the study data by comparing the data filed with the agency

or the sponsor, if available, with records related to the clinical investigation. Such records may

include the case report forms and supporting source documentation including signed and dated

consent forms and medical records including, for example, progress notes of the physician, the

subject’s hospital chart(s), and the nurses’ notes. These records may be in hard copy and/or an

electronic format. For electronic records and/or electronic signatures, the FDA investigator may

gather information to determine whether 21 CFR part 11 requirements have been met. FDA may also examine subjects’ medical records that are part of the clinical investigation and

predate the study to verify whether the condition under study was in fact diagnosed, the study

eligibility criteria were met, and whether the subject received any potentially interfering

medication prohibited by the protocol.

The FDA investigator may also review subjects’ records  covering a period after completion of study-related activities to determine if there was proper  follow-up as outlined in the protocol, and if the clinical investigator submitted all reportable  adverse events (including all clinical signs and symptoms). See 21 CFR 312.64(b) and  812.150(a). For more information about the procedures FDA uses during inspections of clinical  investigator sites, see FDA’s Compliance Program Guidance Manual (CPGM), Bioresearch Monitoring, Clinical Investigators and Sponsor-Investigators, Program 7348.811.5.

INTERNATIONAL INSPECTIONS

FDA’s inspection of clinical investigators is not limited to the United States (U.S.). International

inspections are generally conducted when the studies are part of a marketing application

submitted to FDA and provide data critical to decision-making on product approval. See FDA’s

CPGM, Program 7348.811, “Clinical Investigators and Sponsor-Investigators.”6

 Such  assignments include studies that are conducted under an FDA investigational new drug

application (IND), as well as studies at non-U.S. sites that are not conducted under an IND or

under an investigational device exemption (IDE).

(Ref: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126553.pdf)

EU

EU harmonisation

The European Medicines Agency plays an important role in the harmonisation and co-ordination of GCP-related activity at an EU level. It is involved in:

co-ordinating GCP inspections for the centralised procedure;

preparing guidance on GCP topics through the work of the GCP Inspectors Working Group;

co-ordinating advice on the interpretation of EU GCP requirements and related technical issues;

developing of EU-wide guidelines on GCP inspections and related procedures for the centralised procedure.

For more information on clinical trial authorisation, safety monitoring, GCP inspections, and GCP and GMP requirements for clinical trials in the European Economic Area (EEA), see volume 10: clinical-trial guidelines of the rules governing medicinal products in the EU.

International clinical trials

Regardless of where they are conducted, all clinical trials included in applications for marketing authorisation in the EEA must be in accordance with:the GCP Directive (Directive 2001/83/EC Annex I, as amended by Directive 2003/63/EC);the ethical standards of the Clinical Trials Directive (Directive 2001/20/EC).

In July 1996, the EU adopted the guideline for good clinical practice, which lays out unified GCP standards for Europe, the United States of America and Japan.The Council for International Organizations of Medical Science (CIOMS);the World Medical Association.

Clinical trials conducted in countries outside the EU

The number of clinical trials and clinical-trial subjects outside Western Europe and North America has been increasing for a number of years. The Agency has been tracking the geographic origins of patients included in pivotal trials submitted in marketing authorisations to the centralised procedure.

In April 2012, the Agency published the final version of the reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of the EU / EEA and submitted in marketing authorisation applications to the EU regulatory authorities. The aim of the paper is to strengthen existing processes to provide assurance to regulators and stakeholders that clinical trials meet the required ethical and GCP standards, no matter where in the world they have been conducted.

The reflection paper is part of the Agency’s strategy developed to address the challenges arising from the increasing globalisation of clinical research. These challenges are addressed in a two-fold manner, by: putting forward concrete steps for international cooperation between regulatory authorities in the regulation of clinical trials, with a specific emphasis on capacity-building initiatives for a common approach to oversight of trials and to ensure a robust framework for the oversight and conduct of clinical trials;clarifying and determining the practical steps by which EU regulators will gain assurance that ethical and GCP standards are applied to clinical trials for human medicines, both during the development and during the marketing-authorisation-application phase.

Working Group on Clinical Trials conducted outside of the EU / EEA

The Agency's Working Group on Clinical Trials Conducted Outside of the EU / EEA was established in 2009 to develop practical proposals for tasks and procedures or guidance  in the four areas identified in the strategy paper on the acceptance of clinical trials conducted outside of the EU/EEA:clarify the practical application of ethical standards for clinical trials, in the context of the Agency's activities;determine the practical steps to be undertaken during the provision of guidance and advice in the drug-development phase;determine the practical steps to be undertaken during the marketing-authorisation phase;international cooperation in the regulation of clinical trials, their review and inspection and capacity building in this area and to develop a reflection paper on ethical and GCP aspects of clinical trials conducted outside the EU / EEA.

The Working Group includes representatives of the Committee for Medicinal Products for Human Use (CHMP), Paediatric Committee (PDCO), Committee for Orphan Medicinal Products (COMP), Coordination Group for Mutual Recognition and Decentralised Procedures (CMD), Clinical Trials Facilitation Group, GCP inspectors, Patients' and Consumers' Working Party, Healthcare Professionals' Working Group, Agency secretariat and European Commission.

The Working Group meets on a regular basis at the Agency. Collaboration with the Food and Drug Administration The Agency and the United States Food and Drug Administration (FDA) agreed to launch a joint initiative to collaborate on international GCP inspection activities in July 2009.

The initiative forms an important contribution to ensuring the protection of clinical-trial subjects in the context of the increasing globalisation of clinical research. The initiative comes under the scope of the confidentiality arrangements between the European Commission, the European Medicines Agency (EMA) and the FDA. For more information on these arrangements, see United States.

EMA-FDA GCP initiative

GCP initiative: frequently asked questions and answers

The initiative's main objectives are to:

conduct periodic information exchanges on GCP-related information, to streamline sharing of GCP inspection planning information, and to communicate on inspection outcomes effectively and in a timely manner;

conduct collaborative GCP inspections by sharing information, experience and inspection procedures, co-operating in the conduct of inspections and sharing knowledge of best practice;

share information on the interpretation of GCP, by keeping each other informed of GCP-related legislation, regulatory guidance and related documents, and to identify and act together to benefit the clinical research process.

The initiative began with a pilot phase that ran between September 2009 and March 2011. During the pilot, the EMA and the FDA exchanged more than 250 documents relating to 54 different medicines. They also organised 13 joint inspections of clinical trials in conjunction with the GCP inspectors of the EU Member States.

A report and question-and-answer document on the outcomes of the pilot are available, which detail the success of the information-sharing and collaboration on inspections relating to clinical trials:

Report of the EMA-FDA pilot GCP initiativeQuestions and answers on the EMA-FDA GCP initiative

The pilot has laid the foundation for a more efficient use of limited resources, improved inspection coverage and better understanding of each agency’s inspection procedures. It demonstrates how the agencies can work together to improve human subject protection and better ensure the integrity of data submitted as the basis for drug approvals.

Based on the positive experience, the EMA and the FDA intend to continue with the initiative, incorporating lessons learned during the pilot. The agencies are updating the terms of engagement and procedures for participating authorities to reflect this.Applicants interested in volunteering to take part in a collaborative inspection during the pilot phase should contact the EMA or the FDA.

(ref:http://www.emea.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000072.jsp&mid=WC0b01ac05800268ad)

Overview Recent developments

The Food and Drug Administration (FDA) is responsible for deciding whether new human drugs and therapeutic biologics can be marketed in the United States. Given the substantial investment of time and resources required to bring a drug or biologic to market, clinical trial sponsors closely scrutinize application reviews, seeking to understand the factors that influence FDA’s decisions to approve or deny a New Drug Application (NDA) or Biologics License Application (BLA). In particular, sponsors’ perceptions of what inspectional findings bring data integrity into question and lead to refusal to approve an application may influence how they plan, conduct and oversee their trials.

Within the Center for Drug Evaluation and Research (CDER), the Division of Scientific Investigations (DSI) in the Office of Compliance has specific responsibility for overseeing the inspections that verify the integrity of application data and determine whether clinical trials supporting applications are conducted in compliance with current FDA regulations and statutory requirements. To provide insight into how DSI verifies whether data are of sufficient quality to support conclusions drawn in an NDA or BLA, we completed an analysis of our application review documentation from first quarter (1Q) fiscal year (FY) 2010 through 1Q FY 2011, covering the most recent time period for which we had complete data. We also evaluated documentation related to our decisions to classify clinical investigator inspections as “official action indicated” (OAI) during the same time period, focusing on factors that might lead to a recommendation to reject data in this subset of inspections

DSI’s Role in Drug Approval

Data supporting each NDA or BLA that CDER receives undergoes multi-disciplinary review. During this review, DSI collaborates with reviewers in CDER’s Office of New Drugs (OND) to identify inspections important to determining that data supporting efficacy and safety conclusions are accurate and complete. Ultimately, DSI reviews a subset of submitted original and supplemental NDAs and BLAs. Over the past five years, DSI has overseen approximately 480 on-site inspections of clinical investigators, clinical trial sponsors and contract research organizations (CRO) annually. Of these, approximately 70 percent were conducted as part of NDA or BLA review, with the remainder arising from complaints concerning the various parties engaged in FDA-regulated research.

Selection of sites for NDA and BLA-related inspections is generally based upon a site’s importance to the data supporting an application, such as the number of subjects enrolled or the site’s relative contribution to study efficacy conclusions. Where an application relates to a new molecular entity, FDA generally inspects the sponsor in addition to the clinical investigator sites. More recently, CDER has been piloting a risk-based clinical investigator site selection tool that permits quantitative evaluation of an array of factors that may indicate a higher risk of data integrity concerns at a site. FDA may also conduct sponsor and CRO inspections in response to site-level inspectional findings that indicate possible deficits in sponsor or CRO oversight.

Once sites are selected, DSI issues inspection assignments to field investigators within FDA’s Office of Regulatory Affairs who carry out the on-site inspections. On occasion, DSI reviewers may participate in the inspection as clinical and/or scientific expert consultants. However, a DSI reviewer’s primary role during NDA and BLA review is to critically evaluate inspectional findings and their overall impact on site and study data integrity and human subject protections.

When a field investigator observes conditions during an inspection that he/she believes constitute a regulatory violation, the field investigator will recommend an action, taking into consideration the nature of the inspectional findings, any actions that occurred following the findings and agency policy. DSI reviews the recommended action, determines whether is the action is appropriate and supported by adequate evidence and makes a final decision about the inspection classification. Depending on the nature of the violations, FDA may ultimately find that corrective action may be left to the establishment to take voluntarily (voluntary action indicated, or VAI). Alternatively, FDA may determine that regulatory and/or administrative sanctions are necessary to more immediately address significant objectionable conditions or practices and classify the inspection as OAI. OAI actions may range from issuance of a warning letter to pursuit of disqualification of a clinical investigator.

In addition to reviewing the outcomes of individual inspections to determine appropriate action for the inspected entity, DSI reviewers also consider whether and how inspectional findings inform FDA’s conclusions about the reliability of data in a marketing application. For this analysis, reviewers generally focus on the data most critical to important conclusions about a product’s safety and efficacy.1 A Clinical Inspection Summary (CIS) memo documents DSI’s formal recommendations to the OND review division at two levels: (1) whether DSI considers data from an individual clinical investigator or another inspected party reliable, taking into account the nature, extent, clinical significance and possible root causes of any observed noncompliance and (2) whether DSI, after careful review of findings across inspections, considers data from the clinical investigation as a whole reliable in support of a proposed indication. The analysis below is intended to shed light on this review process.

(ref: http://www.fdli.org/resources/resources-order-box-detail-view/current-trends-in-fda-inspections-assessing-clinical-trial-quality-an-analysis-of-cder-s-experience)

Current issues in Clinical research

Clinical Trial Billing Issues

1. Interpretation of Medicare clinical trial policy
2. Sponsors as secondary payers to insurance
3. Process issues
4. Medicare : July 2007 National Coverage Decision (NCD)
5. Qualifying Trials: Trial must “qualify” for coverage:

Four requirements to qualify:

The trial must be “deemed” to have desirable characteristics (based on funding source)

The investigational item or service must fall within a Medicare benefit category

The study must enroll patients with diagnosed disease

The study must have therapeutic intent

Regional Medicare contractor’s Medical Director determines which trials/what factors constitute therapeutic intent

Phase I trials probably will not qualify

You need to speak with your Medicare contractor’s Medical Director

Routine Costs: Medicare pays for “routine costs”

Conventional Care/SOC

Items/services required for provision of the investigational item or drug

e.g., administration of chemotherapeutic agent

Items/services for the detection and prevention of complications

What about standard of care services for a trial that does not qualify?

Ask your Medical Director if billable

6. Sponsors as Secondary Payers: Cannot bill Medicare if a sponsor agrees to pay for a service if an insurer (including Medicare) first denies the claim
7. If you bill insurance and claim denied, you must pursue payment from patient
8. Exceptions for indigent patients
9. See CMS SE0822 (released Sep 2008 and modified Jan 09) 

Institutional Stance/Policies: Must have an institutional policy Some issues open to interpretation –institution needs to take a stance Research personnel must be trained on the policy

Process Issues: The complicated part!

Form a cross-functional team:

revenue cycle

research teams

Sponsors programs

Billing system IT experts

Executive support necessary for success

Process Team: The team will:

Examine current processes and information flows

Develop processes to ensure compliant billing

Implement processes

Monitor progress – are the new processes working? 

Don’t just disband and assume everything will work swell!

Clinical Research Coordinators:  Researchers and Study Financial Administrators

Current Issues in Clinical Trials Contracting

(ref: www.ncura.edu)

Confidentiality issues

Researchers in the biomedical as well as social and behavioral sciences are expected

to be proactive in designing and performing research to ensure that the dignity, welfare,

and privacy of individual research subjects are protected and that information about an

individual remains confidential. This expectation is expressed in the ethical codes of

conduct of professional societies. Protecting the confidentiality of information collected

about individuals is also vital to fulfilling the ethical responsibilities described in the

Belmont Report.

Research in the biomedical and social sciences encompasses a broad array of topical

areas, designs, and degree of risk. Many studies pose minimal risk to research

subjects. Some studies, however, are inaccurately perceived as conveying minimal

risk. In such studies, disclosure of identifiable data may present a significant risk to the

subject as a result of the sensitive nature of the topic, the variety of social interactions,

or possible financial or legal implications of the activity being studied. In such research,

especially in the social and behavioral sciences, protecting the confidentiality of data

collected from or about private individuals is often the key element in minimizing risk.

In addition to protecting research subjects from harm that might result from their

participation in research, applying appropriate confidentiality protections provides other

important benefits. Confidentiality protections minimize subjects’ concerns over the use

(or misuse) of the data. Subjects consequently provide more accurate information to

investigators, thereby improving the data used in the analysis and thus the overall

quality of the research. Confidentiality protections allow researchers to continue to

conduct difficult research on important societal problems (e.g., drug abuse, the spread

of HIV, genetic predispositions, high risk sexual behaviors, violence). Such research

provides a scientifically-informed basis for making important public policy decisions and

fosters advances in medicine and in all fields of science. The benefits of these results

accrue not only to the research subjects, but to society at large.

Confidentiality issues need to be recognized and considered at every stage of the

research process. These stages include the initial study design; identification,

recruitment, and consent processes for the study population; security, analysis, and

final disposition of data; and publication or dissemination of data and results.

Intentional or inadvertent breaches of confidentiality by investigators or their staff may

occur. In addition, there may be attempts (usually in a legal context) to force or compel

disclosure of confidential information for non-research purposes. The likelihood of such

an attempt cannot be anticipated by virtue of the subject matter or setting of the

research. [An informative overview of this issue can be found in Joe S. Cecil and

Gerald T. Wetherington, Special Editors, Court-Ordered Disclosure of Academic

Research: A Clash of Values of Science and Law. 59 LAW AND CONTEMPORARY

PROBLEMS. Number 3, Summer 1996.] The purpose of this paper is not to address all

dimensions of this issue, but to focus on those aspects that are especially important in

protecting against breaches of confidentiality.

Reducing Risk Through Confidentiality Protections

Confidentiality issues do not inhere in all human subjects research. For example,

observation of behavior in public places where there is no interaction between the

observer and the observed and where data are recorded in anonymous form involves

no issue of confidentiality for subjects, investigators or IRBs. In some studies, the

consent agreement establishes that research subjects neither seek nor want

confidentiality (e.g., a political science study of legislative changes where directors of

interest groups agree to participate knowing that what they report will be presented as

part of the analysis of factors leading to change). In circumstances where a promise of

confidentiality is not a part of an informed consent agreement, the protocol makes clear

to IRBs the nature of the consent agreement and why biographical anonymity and

confidentiality are not sought.

Issues of data confidentiality typically come into play when biomedical, social or

behavioral science research involves data collection on identifiable individuals.

Confidentiality protections should be developed consistent with the study design and the

potential risk of harm from breaches of confidentiality. As the risk of harm incurred by

disclosure increases, so should the level of protection from such harm. In some cases,

the collected data may not require as high a level of security as in other cases (e.g.,

laboratory studies on the level of boredom associated with repetitive tasks does not

involve the same risk of data disclosure as surveys of personal sexual orientation and

experience; clinical laboratory data generally do not involve the same risk of disclosure

as data from genetic testing or screening). In all cases where a promise of confidentiality is included in the consent agreement, it must be granted and

secured—regardless of the level of risk.

Much of the risk in social and behavioral science research is related to inadvertent or

unintended disclosure. An adequate data protection plan can and should reduce the

risk of such occurrences. The OHRP has clarified that the Common Rule allows

institutions and IRBs the flexibility to review and approve appropriately designed

confidentiality protections.

Protocols should be designed to minimize the need to collect identifiable data by

determining whether there is a legitimate reason to collect or maintain identifiers. Data

can often be collected anonymously, or the identifiers can be removed and destroyed

after various data have been merged. When it is necessary to collect and maintain

identifiable data, a data protection plan should describe the appropriate level of

confidentiality protections based on the potential magnitude of the risk of harm from

disclosure. All members of the research team and staff should receive appropriate

training about securing and maintaining confidentiality and safeguarding data. Data

should be physically secure, and all identifiable, confidential data not intended for

secure archiving should be destroyed.

Confidentiality Protections

Efforts can and should be made to buffer or insulate research data from encroachment.

When a determination is reached that the sensitive nature of the data and the potential

risk of harm to individual subjects occasion legally supported confidentiality protections,

the investigator (with the support of the institution) should pursue appropriate

protections.

One such mechanism involves securing a certificate of confidentiality from the

Department of Health and Human Services for applicable categories of research

(biomedical, behavioral, clinical, mental health, drug or alcohol abuse)..

 Another involves investigator and institutional compliance with mandatory confidentiality

protections such as those provided through statutes covering the DOJ and DOEd.. It is

important to note that each of these confidentiality provisions has important limitations.

It may apply only to certain categories of research or to research sponsored by a

specific agency. It may protect the identity of the research subject, but not the data.

Or, it may provide protection against compelled disclosure of data, but not voluntary

disclosure . OHRP should lead efforts to strengthen the  current system of confidentiality protections.

Given the limits of these statutory protections, both investigators (and their research

teams and staff) and their institutions are morally obligated to resist attempts to breach

confidentiality through compelled or forced disclosures (e.g., subpoenas). This not only

fulfills ethical obligations to the research subject, but also serves to prevent important

breaches of confidentiality. It is important to note that courts may subpoena either data

or investigators who have had conversations with participants.

(Ref: http://www.hhs.gov/ohrp/archive/nhrpac/documents/nhrpac14.pdf)

Medicines for human use ( clinical trials ) regulations 2004

PART 1 INTRODUCTORY PROVISIONS

1.Citation and commencement

2.Interpretation

3.Sponsor of a clinical trial

4.Responsibility for functions under the Directive

Collapse -PART 2 ETHICS COMMITTEES

5.United Kingdom Ethics Committees Authority

6.Establishment of ethics committees

7.Recognition of ethics committees

8.Revocation of recognition

9.Constitution and operation of ethics committees

10.Other functions of the Authority

Collapse -PART 3 AUTHORISATION FOR CLINICAL TRIALS AND ETHICS COMMITTEE OPINION

11.Interpretation of Part 3

12.Requirement for authorisation and ethics committee opinion

13.Supply of investigational medicinal products for the purpose of clinical trials

14.Application for ethics committee opinion

15.Ethics committee opinion

16.Review and appeal relating to ethics committee opinion

17.Request for authorisation to conduct a clinical trial

18.Authorisation procedure for clinical trials involving general medicinal products

19.Authorisation procedure for clinical trials involving medicinal products for gene therapy etc.

20.Authorisation procedure for clinical trials involving medicinal products with special characteristics

21.Clinical trials conducted in third countries

22.Amendments to clinical trial authorisation

23.Amendments by the licensing authority

24.Amendments by the sponsor

25.Modifying or adapting rejected proposals for amendment

26.Reference to the appropriate committee or the Medicines Commission

27.Conclusion of clinical trial

Collapse -PART 4 GOOD CLINICAL PRACTICE AND THE CONDUCT OF CLINICAL TRIALS

28.Good clinical practice and protection of clinical trial subjects

29.Conduct of trial in accordance with clinical trial authorisation etc.

30.Urgent safety measures

31.Suspension or termination of clinical trial

Collapse -PART 5 PHARMACOVIGILANCE

32.Notification of adverse events

33.Notification of suspected unexpected serious adverse reactions

34.Clinical trials conducted in third countries

35.Annual list of suspected serious adverse reactions and safety report

Collapse -PART 6 MANUFACTURE AND IMPORTATION OF INVESTIGATIONAL MEDICINAL PRODUCTS

36.Requirement for authorisation to manufacture or import investigational medicinal products

37.Exemption for hospitals and health centres

38.Application for manufacturing authorisation

39.Consideration of application for manufacturing authorisation

40.Grant or refusal of manufacturing authorisation

41.Application and effect of manufacturing authorisation

42.Obligations of manufacturing authorisation holder

43.Qualified persons

44.Variation of manufacturing authorisation

45.Suspension and revocation of manufacturing authorisation

Collapse -PART 7 LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCTS

46.Labelling

Collapse -PART 8 ENFORCEMENT AND RELATED PROVISIONS

47.Application of enforcement provisions of the Act

48.Infringement notices

49.Offences

50.False or misleading information

51.Defence of due diligence

52.Penalties

Collapse -PART 9 MISCELLANEOUS PROVISIONS

53.Construction of references to specified publications

54.Consequential and other amendments to enactments

55.Revocations

56.Transitional provisions

Signature

SCHEDULES

1.Conditions and principles of good clinical practice and the protection of clinical trial subjects

2.Additional provisions relating to ethics committees

3.Particulars and documents that must accompany an application for an ethics committee opinion, a request for authorisation, a notice of amendment and a notification of the conclusion of a trial

4.Appeal against unfavourable ethics committee opinion

5.Procedural provisions relating to the refusal or amendment of, or imposition of conditions relating to, clinical trial authorisations and the suspension or termination of clinical trials

6.Particulars that must accompany an application for a manufacturing authorisation

7.Standard provisions for manufacturing authorisations

8.Procedural provisions relating to proposals to grant, refuse to grant, vary, suspend or revoke manufacturing authorisations

9.Modification of the enforcement provisions of the Act subject to which those provisions are applied for the purposes of these Regulations

10.Consequential and other amendments of enactments

11.Revocations

12.Transitional provisions

Other relevant issues

Challenges in Clinical Research

Cooperation among a diverse group of stakeholders—including research sponsors (industry, academia, government, nonprofit organizations, and patient advocates), clinical investigators, patients, payers, physicians, and regulators—is necessary in conducting a clinical trial today. Each stakeholder offers a different set of tools to support the essential components of a clinical trial. These resources form the infrastructure that currently supports clinical research in the United States. Time, money, personnel, materials (e.g., medical supplies), support systems (informatics as well as manpower), and a clear plan for completing the necessary steps in a trial are all part of the clinical research infrastructure. A number of workshop participants lamented that most clinical trials are conducted in a “one-off” manner.The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control1 Significant time, energy, and money are spent on bringing the disparate resources for each trial together. Some workshop attendees suggested that efficiencies could be gained by streamlining the clinical trials infrastructure so that those investigating new research questions could quickly draw on resources already in place instead of reinventing the wheel for each trial.

Challenges Facing Investigators in Academic Health Centers

Woodcock discussed a number of important obstacles facing investigators conducting research using the current infrastructure. Clinical investigators, those who lead a research idea through the clinical trial process, face multiple small obstacles that together can appear insurmountable. These obstacles include locating funding, responding to multiple review cycles, obtaining Institutional Review Board (IRB) approvals, establishing clinical trial and material transfer agreements with sponsors and medical centers, recruiting patients, administering complicated informed consent agreements, securing protected research time from medical school departments, and completing large amounts of associated paperwork. As a result of these challenges, many who try their hand at clinical investigation drop out after their first trial. Especially in the case of investigator-initiated trials, where an individual’s idea and desire to explore a research question are the primary force behind the trial, the complex task of seeing a clinical trial through from beginning to end is making the clinical research career path unattractive for many young scientists and clinicians. Woodcock noted that in her experience, successful clinical investigators represent a select subset of clinicians—highly tenacious and persistent individuals with exceptional motivation to complete the clinical trial process.

According to Robert Califf, Vice Chancellor for Clinical Research and Director of the Duke Translational Medicine Institute, some of the challenges to participating in clinical research mentioned by clinical cardiovascular investigators include:

1. the time and financial demands of clinical practice;
2. the overall shortage of cardiovascular specialists;
3. the increasing complexity of regulations;
4. the increasing complexity of contracts;
5. the lack of local supportive infrastructure;
6. inadequate research training;
7. less enjoyment from participation (e.g., increasing business aspects, contract research organization pressures); and
8. data collection challenges (medical records, reimbursement, quality control, pay for performance).

Challenges Confronting Community Physicians

Practitioners face a number of challenges to their involvement in clinical research. Busy patient practices and the associated billing and reporting requirements leave them with limited time for research. A further barrier is the lack of a supportive clinical research infrastructure, especially in the form of administrative and financial support. For practitioners who become engaged in running a clinical trial and recruiting patients, their financial reimbursement per patient can, in some cases, be less than they would receive from regular practice. In addition, there is a financial disincentive for physicians to refer their patients to clinical trials. Physicians who do so must often refer those patients away from their care; thus each patient referred represents a lost revenue stream.

Challenges Facing Patients

Patients also face challenges to participating in clinical research. Many workshop participants noted that patients often are unaware of the possibility of enrolling in a clinical trial. If they are aware of this opportunity, it is often difficult for them to locate a trial. Patients may reside far from study centers; even the largest multicenter trials can pose geographic challenges for those wishing to participate. Moreover, depending on the number of clinic visits required by the study protocol, significant travel and time costs may be associated with participation. In addition, trials designed with narrow eligibility criteria for participation purposely eliminate many patients who might have the disease being studied but are ineligible because of other characteristics (e.g., age, level of disease progression, exposure to certain medicines).

Informed Consent

Informed consent refers to the process and documents associated with educating individuals on the details of a clinical trial and potentially gaining their consent to participate in the study.The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.Destroy user interface control5 Obtaining informed consent from each subject in a clinical trial requires a significant amount of time. The informed consent process includes developing appropriately worded consent documents, discussing the documents and the clinical trial process with individual patients, obtaining the required patient signatures on the documents, and keeping track of the paperwork generated throughout the enrollment process.

Patient Education

Mayer presented the results of a Harris Interactive Survey of 6,000 cancer patients that found that 85 percent were unaware that participation in clinical trials was even an option. Of the patients surveyed, 75 percent said that if participation in a clinical trial had been offered, they would have been receptive to the idea. Of those aware of clinical trials and offered the possibility of participation, 71 percent chose not to participate. However, almost all who participated were satisfied with the experience. Thus, according to these survey results, patients’ preconceived notions about trial participation could pose a barrier to clinical trial enrollment.

Patient Recruitment

According to Woodcock, sites for clinical trials are frequently selected on the basis of where the investigators are located, as opposed to where the patients are, creating difficulties in patient recruitment. When patient recruitment is impeded, the trial is delayed, sometimes by years, until the number of patients required by the study protocol can be enrolled. Once a trial protocol has been activated, the recruitment of patients requires a significant amount of time and money. Canetta reported that the ability to recruit patients into a trial successfully is similar for the pharmaceutical industry and NCI. Regardless of the trial sponsor, recruitment of patients who meet the requirements of the protocol is difficult: in one study of 14 cancer centers approximately 50 percent of study sites failed to recruit a single patient (Durivage et al., 2009). Thus, patient enrollment can directly affect the number of trials that are completed.

(ref: http://www.ncbi.nlm.nih.gov/books/NBK50888/)