Clinical research is currently in the news for its immense business potential in India. Besides the IT sector, clinical research is also sought after for outsourcing by the US & European healthcare sector. The current 30 million US dollar business is likely to increase ten fold by the year 2010. Among the various factors, contributing to this upward swing is the patient enrollment rate (0.3 patients per month in US as against 3 patients in India during the same period) and the lower cost of research in the Indian setting. The only possible hurdle, which could seriously hamper such a development is the apprehension in the minds of outsourcing companies about the quality of data & acceptance of such data by the global regulatory authorities, in general and the US FDA, in particular. And this apprehension stems from the fact that only a fraction of about 500,000 doctors are trained in ICH-GCP, which could mean inadequate documentation and inaccurate safety profiling of the New Chemical Entity (NCE).

According to the US FDA Federal Regulation of 1938, establishing the safety of a new molecule is a pre-requisite for obtaining a marketing approval. This was further corroborated by the infamous Thalidomide tragedy (phocomelia among pregnant women) in 1962, which amply demonstrated that the “Safety” consideration must take precedence over the “Efficacy” consideration of NCE. Ever since, all the regulators and healthcare authorities, worldwide have established very stringent codes for conducting clinical trials. These guidelines have undergone constant evolution, starting from the Helsinki declaration adopted by the World Medical Assembly (WMA) in 1964 to the current ICH-GCP guidelines. The only aim of these directives is to safeguard the rights and wellbeing of the trial subjects.

“Efficacy” of a new molecule can be demonstrated through ‘positive findings’ (results) that indicate its therapeutic usefulness. On the other hand “Safety” of the new molecule can only be established by its ‘lack of relative risk’ to the patients. This can be done only if the trial subjects on study medications are closely and diligently monitored for ‘possible’ adverse experiences during the study. An Adverse Drug Reaction (ADR) is defined as “Any untoward medical occurrence in a patient or a clinical trial subject, administered a medicinal product, and which does not necessarily have a causal relationship with this treatment”. The timely and continuous analysis of the safety and efficacy data in terms of ‘Risk/Benefit Ratio’ of the NCE is very critical to the conduct of the study involving the new molecule.

It is important that irrespective of the causality assessment, all adverse events experienced (and not only ADRs, where causality is implied) are monitored, documented adequately and accurately and then reported in a pre-decided timely manner.


Indian Scenario

With the latest amendment (dated 20th Jan 2005) to the Schedule Y of Drugs and Cosmetic Act 1945, the reporting of adverse events from clinical trials has become clearer and unambiguous. There is of course a quantum leap between the old and the new version and the serious intentions of the Drug Controller General of India (DCGI) regarding stricter compliance are clearly palpable.

According to the amended Schedule Y, the responsibilities of the sponsors vis-a-vis safety reporting are given in clause 2; which are as follows:
“Any unexpected serious adverse event (SAE) (as defined in GCP Guidelines) occurring during a clinical trial should be communicated promptly (within 14 calendar days) by the Sponsor to the Licensing Authority and to the other Investigator(s) participating in the study.
Whereas the responsibilities of the Investigator(s) vis-a-vis safety reporting are given in clause 3, which are as follows:
“Investigator(s) shall report all serious and unexpected adverse events to the Sponsor within 24 hours and to the Ethics Committee that accorded approval to the study protocol within 7 working days of their occurrence”.

The differences between both the versions, w.r.t sponsors’ reporting obligations are summarized in the following.
New Schedule Y : All ‘unexpected SAEs’ within 14 calendar days would be communicated to the local regulatory authority & other participating investigators”.
Old Schedule Y : “Any unusual, unexpected or serious adverse reaction to be communicated promptly to the local regulatory authority”.

While we must appreciate the clarity and unambiguity of the new Schedule Y, issues such as unblinding, submission of the “foreign cases” from the multinational clinical trials, and guidelines for tackling ADRs associated with comparator drugs or with placebo need to be further addressed. If one goes by the strict interpretation of the text, the investigators are not supposed to submit to the sponsors, in an expedited manner, the ‘Serious Adverse Events/Reactions’ that are expected?
One must appreciate the DCGI’s spirit in diverging from the ICH & CIOMS guidelines in insisting on reporting, ‘Unexpected Serious Events’ (double yes cases) in order to usher in ‘reporting culture’ in India (against the internationally accepted norm of reporting ‘Suspected Unexpected Serious Adverse Reactionss (SUSARs) – triple yes cases to regulatory authorities of the world). It would also be worthwhile to have a look at the international scenario and the most recent recommendations from CIOMS working group VI, in this connection.

International Scenario

Most of the regulations that describe safety reporting from clinical trials, focus on the expedited reporting of the individual case safety reports (ICSRs). ICH Guidelines E2A, which is generally considered the standard for the information to be sent, stipules that sponsors should submit suspected adverse drug reactions that are both serious and unexpected to the regulators within 7 (if fatal or life threatening) or 15 calendar days in an appropriate format.

Expedited single case reports from CTs are accepted by majority of the Regulatory Authorities (RAs) on the CIOMS I or similar form. With the adoption of ICH Guidelines E2B and then E2B(M), which define standard data elements for electronic ICSRs, some RAs have begun to require the electronic submission of expedited reports in the post marketing scenario. More recently, the European Union (EU) and Japan have begun requiring electronic submission of the expedited reports from CTs as well. While the time frames and reporting criteria for expedited reporting are mostly consistent across the regions, there are authorities which require expedited reporting of suspected SADRs, regardless of ‘expectedness’. The CIOMS VI Working Group endorses the ICH Guidelines E2A for expedited reporting and recommends that, “Under exceptional circumstances and on an ad hoc basis, should sponsor be expected to report on an expedited basis SADRs that are considered expected”.

Country Requirements for Expedited Reporting US SUL (serious unexpected local)+SUF (serious unexpected foreign) UK SUL + SUF Japan SUL+SEL (serious expected local)+SUF; also SEF if fatal or life threatening France SUL+SUF+SAEs having potential effect on trial designs (if studied in France)

As evident from the table, it is only ‘SUSARs’, need to be reported to the regulators expeditedly, in the above named countries, with the lone exception of Japan.

It is interesting to note the latest recommendations of CIOMS VI Working Group are contrary to the common belief and understanding, which favours over-reporting. It states that “The group does not believe that increasing the number of expedited reports, by lowering the threshold for considering an adverse event a suspected adverse reaction, would contribute to the protection of trial subjects or to the overall assessment of safety. To the contrary individual case reports are generally not an effective means of communicating important new safety information. The CIOMS VI Working Group recommends that regulators adopt the phrase “a reasonable possibility of a causal relationship” and consider dropping the phrase “ a causal relationship cannot be ruled out” from the definition of suspected adverse reaction.

The wisdom of these recommendations immediately come to the fore when one realizes that the Indian pharma industry has ended up submitting weird unrelated cases to the DCGI’s office, such as hip fracture, nerve injury involving machine accident, enteric fever (all from Cardiovascular Studies), and also a case of cardiac arrest in a patient who was randomized but was never administered any study medication???


Institutional Review Boards (IRBs) & Ethics Committees (ECs)

Current rules encourage researchers and sponsors to report all "unexpected," "serious" & "related" adverse events to a number of parties, including IRBs, since there is a general agreement that IRBs/ECs should primarily be responsible for ensuring the safety of research participants enrolled in studies under their auspices. These policies worked well when most clinical studies were conducted at a single site, but they are wreaking havoc with the increase in multi-site investigations involving dozens of researchers and thousands of participants. Most observers recognize that IRBs also need to be aware of unanticipated problems elsewhere that could affect local studies. The problem is that all investigators involved in a multi-centre trial send adverse events to all other investigators, who then file this information with their local IRB. And hence they become the automatic recipients of all the ICSRs of not only the unexpected SAEs, (as per the new Schedule Y) occurring at their own sites, but from other sites as well. In addition they also keep getting a plethora of 15 days IND safety alerts (foreign triple yes cases). As a result, a single event can generate multiple reports to multiple organizations - all obliged to examine and assess the information. The aim of this approach is to alert investigators to possible problems arising among study participants at other sites. It similarly may be helpful for IRBs and investigators to know that an adverse event from a local trial has occurred elsewhere.

The magnitude and complexity of the task, of each IRB/EC in evaluating and arriving at a correct decision, vis-à-vis benefit/risk of the ongoing study, can be gauged from the example of ‘The Western Institutional Review Board’. According to Executive Director Owen Reese, the board receives 12,000 AERs from sites and 14,000 from sponsors each year, with 70% of these reports identified as "not related" to the study at hand. The University of Pennsylvania similarly gets some 13,000 reports each year from industry sponsors via Penn investigators, compared to about 250 research safety reports each week for its own studies. Yvonne Higgins, director of Penn's Office of Regulatory Affairs, said that her office instructed investigators not to file all those redundant sponsor reports. But the researchers insisted that FDA regulations required them to do so.

Pragmatic Approaches (Recommendations and Proposals)

A number of proposals for improving AER quality and for limiting report volume were presented at the FDA meeting by sponsors, IRBs, research organizations, investigator groups, and others, demonstrating the complexity of the issue, some of which can be summarized as follows:
* Establishing a central IRB for multisite studies that would receive and analyze all AERs. Local IRBs would be responsible for assessing only those AERs filed by its investigators, which then would be sent on to the central IRB.
* Sponsors to provide periodic (probably quarterly) summaries of all other AERs to IRBs and investigators, in addition to the annual reports required by FDA. However, some IRB officials feel that sponsors are not sufficiently objective to handle this task and that a third party should review safety reports.
* Promoting the concept and the role of independent Data Safety Monitoring Boards (DSMBs) to periodically analyze the safety data and identify new issues, if any. DSMBs recommendations though not mandatory, but may prove decisive in the conduct of the CTS.
On the international front, the Council for International Organizations of Medical Sciences (CIOMS), which has proposed common policies for international post market drug adverse event reporting over the last 20 years, recently moved to consider surveillance and safety reporting related to clinical trials. Last month, the CIOMS VI working group on managing safety information from clinical trials of medicinal products issued a final report offering recommendations for implementing common safety information reporting systems around the world. The report addresses expedited and periodic safety reporting and draws from the provisions in ICH documents, World Health Organization guidelines, and relevant EU directives and guidelines.

The report advises the research community to replace the current practice of sending large numbers of individual case reports to IRBs and IECs. Sponsors instead should submit "periodic and ad hoc communications" to investigators and ECs, with expedited communications focusing on "significant new safety information" that has "implications for the conduct of the clinical trial." This approach follows the European policy of expedited reporting of serious and unexpected suspected adverse reactions (SUSARs), but still leaves it to investigators to decide what events warrant more aggressive reporting.
We have a long way to go and important milestones to achieve before we can contemplate concepts such as centralized ECs, DSMBs and electronic data submissions. The stakeholders must take cognizance of the tremendous challenges they are faced in order to realize the great growth potential of clinical research in India. Diligent compliance and adherence to GCP basics can only be the right beginning before raising the bar higher.

(The author is Affiliate Pharmacovigilance Head, Sanofi-Aventis, India)