Marketing licenses for biotechnological drugs as well as those used in clinical trials are being rejected by India’s apex pharmaceutical regulator, known as the DCGI, or Drugs Controller General of India. In the last year they have tightened the mechanism for approval on all fronts for therapeutic agents. Both domestic and multinational companies are facing much regulatory scrutiny and are often asked to make some changes in order to be approved. It started in July 2010, and many applications/licenses were sent back with deficiency letters.
The result is lengthy delays and the industry is beginning to fume. There are constant complaints about the sudden placement of various bureaucratic hurdles they need to jump through before obtaining approval. The DCGI is well aware of the complaints and state that all delays are due mainly to incomplete applications.
If an application for commercialization is submitted to a regulatory agency in a number of developed countries, including the United States and throughout Europe, and is either incomplete or contains post-approval changes, the marketing approval for that specific product will be rejected. However, the response from the regulatory authority will contain a letter of deficiency. This provides the Sponsor the opportunity to rectify any prior mistakes and then approach the DCGI again. While this does cause a delay for approval, companies should be more appreciative of this strategy rather than withdrawing the product for commercialization.
In the past, the DCGI did not scrutinize the applications as rigorously regarding biotechnology products. However, today numerous companies are striving to introduce more products in the fields of medical device, vaccination and biotechnology. The agency believes more scrutiny is required as companies attempt to inundate the market with products. The regulatory tightening assumed over a majority of the biotechnology products has presented itself at the time where the current biopharmaceutical market is said to start creating massive revenue for a number of the major global drug firms. Therefore, the DCGI needs to ensure that all products are safe for consumption resulting in the current delay in approvals.
Recently Wen* and his colleagues made a case in JCO for why patients with brain tumors should be included in phase I clinical trials. They are argued that most of the reasons that led to the exclusion of these patients in the past were obsolete and should be reconsidered. Below is a summary on why these patients should be considered for phase I trials.
- They are no longer treated with EIAEDs (drugs that usually induced P450 enzyme and affected hepatic metabolism of the agents being tested), and when they rarely are, they are excluded from studies.
- The MTD or maximum tolerated dose determined in phase I trials for systemic cancers is also the maximum-tolerated dose for brain tumors
- The condition of the patients: patients with brain tumors often younger, have generally less co-morbidities, have taken less prior treatments and have an overall better organ function than patients with systemic cancers.
- Their performance status is acceptable and their life expectancy of 4 to 7 months which is often better than most of the other patients participating in phase I that have exhausted all treatment options.
- Studies have shown that there was not an increase risk of CNS hemorrhage even with the use of biologics or the risk was very modest.
- It is possible to differentiate between neurologic symptoms associated with the tumors and neurotoxicity associated with the investigational product.
- The issue of crossing the BBB (blood brain barrier) remains, which is a valid point. However, based on preclinical studies, if there is evidence that the drug can pass through the BBB, there is no reason to exclude patients with primary brain tumors from the phase I study. Conversely, if preclinical studies suggest that drug penetration may be limited, it may be reasonable to consider excluding patients with brain tumors from the phase I study.
The authors concluded that excluding patients with brain tumors will slow our ability to find better treatments for these patients for whom so few effective therapies exist, and potentially means a lost opportunity to identify a responsive tumor type. Temozolomide is one of the few drugs approved for high-grade gliomas, and inclusion of patients with brain tumors into the phase I trial determined the fate of this important agent. Activity was seen in patients with high-grade gliomas, and eventually the drug received approval from the US Food and Drug Administration. If this drug had been evaluated only in systemic cancers, it is unlikely that its activity against primary brain tumors would have been identified, and as a result, one of the few outcome-changing drugs in glioma treatment would not have become an option for patients.
*Patrick Y. Wen, et al, JCO Aug 20, 2011:3211-3213; published online on July 18, 2011; 10.1200/JCO.2011.36.6328.
In May of this year the DCGI issued guidelines to report Serious Adverse Events in India (SAEs), the aim of these guidelines is to standardize and mainstream SAE reporting in this country. Conversely to the FDA, there is no 1571 when submitting an addendum or amendment to the DCGI and therefore, one of the first steps to mainstream SAE reporting was to set up a coversheet to be enclosed with the SAE form to be submitted to the agency. The cover sheet includes standard information related to the study, Clinical trial file number at the DCGI, the sponsor and CRO contact information, the investigational product and investigative site information. Additionally, information related to the SAE, adverse event term, expected or not expected; its causality per investigator and medical monitor assessment, plus a brief narrative. The DCGI also added a box related to the clinical trial category and provided a list of 8 categories to choose from (these range from new entities developed in India, to global clinical trials, various types of biological products, devices etc). The detailed listed is provided within the guidelines document.
Finally, sponsor or their representatives in India (CROs), have to complete an SAE reporting form: “Suspected Adverse Drug Reaction Reporting Form” to be submitted with the cover letter described above and any supportive documentation (laboratory results, discharge summaries, autopsy reports). At this time, CIOMs and/or MedWatch for the same SAE can be included with this SAE reporting form and cover letter, however, the documentation has to be consistent.
The Indian agency has launched a Pharmacovigilance Programme of India for Assuring Drug Safety, the aim of the program over the next 5 years is to ensure that the benefits of use of medicine outweighs the risks and thus safeguard the health of the Indian population and has for key objectives:
- To monitor Adverse Drug Reactions (ADRs) in Indian population
- To create awareness amongst health care professionals about the importance of ADR reporting in India
- To monitor benefit-risk profile of medicines
- Generate independent, evidence based recommendations on the safety of medicines
- Support the CDSCO for formulating safety related regulatory decisions for medicines
- Communicate findings with all key stakeholders
- Create a national centre of excellence at par with global drug safety monitoring standards
The Pharmacovigilance Program of India will be administered and monitored by two committees, a Steering Committee and a Strategic Advisory Committee. The Steering committee includes as chairman Drugs Controller General (India), New Delhi, ex- officio and members from various institutions such as the Pharmacopoeia Commission of India, representatives from the Ministry of Health & Family Welfare, Directorate General Health Services etc.
*CDSCO or Central Drugs Standard Control Organization
A recent paper by W. Al-Refaie et al, in the Annals of Surgery, Vol 254, number 3, Sep 2011 “Cancer Trials versus the Real World in the United States” showed that 0.64% of patients enrolled in clinical trials. Blacks were less likely than whites to enroll in trials (0.48% vs 0.67%, P65 years), early stage cancer, and those with lung or gastrointestinal cancers less likely to be enrolled.
Besides some of the points addressed by the article, it is important to keep in mind that new cancer drugs are developed and tested in patients that have failed all other cancer therapies or standard of care available to them; therefore, suffering from very advanced forms of cancers. Very few new drugs are immediately tested in early stage cancers. The article addressed the example of colorectal cancer, in this particular case, the treatment varies considerably depending on the stage of the disease while stages I to III are mainly treated surgically with the benefit of add on chemotherapy for stages II and III. Chemotherapy with or without biologic agents is the main treatment in stage IV, advanced and/or metastatic disease.
Additionally, the elderly have indeed been excluded from clinical trials as they were expected to develop more severe serious adverse events and therefore not be able to tolerate the new experimental regimen particularly when testing new biologics. Some of these agents have shown, in some cases, higher rates of serious adverse events when pre-existent co-morbidities are present. However, based on recent findings of clinical trials in larger populations including elderly populations, the latter seem to tolerate these regimens as well as younger subjects. During various sessions at ASCO 2011 there were discussions encouraging and highlighting the importance of including elderly populations in clinical trials.
Besides some of the points addressed in the paper, other factors may contribute to low rates of participation in clinical trials and may include advances in standard of care for some cancers, the complexity of study requirements and procedures, the limited clinical research outside of academic settings and the lack of education and public information particularly in minorities that remain distrustful when it comes to clinical trials. However, it is interesting to mention that these issues tend to disappear when conducting clinical trials outside of the US and Western countries. In Emerging countries all patients insured or uninsured, educated or non-educated, academic and private centers participate in clinical trials.
The working relationship between a Sponsor and CRO is dynamic, fluid and ever changing. It is often one of the most crucial decisions a Sponsor needs to make when assessing their clinical and regulatory path in new drug development. Why is it, that like a marriage, some CROs and Sponsors ‘click’ immediately and others face the rocky road of disharmonious discord from day one? There are 5 easy tips for any Sponsor looking at entering into a relationship with an unknown CRO, somewhat like online dating. The Sponsor needs to make sure their CRO is going to fit into the existing dynamic of their company and has the expertise to take their product through the clinical and regulatory pathway.
Tip 1: The Interview. When choosing your CRO make sure you meet all members of the team that are going to be working with you and your team. Evaluate personality types and level of expertise. Don’t judge a CRO on a first time sales pitch or presentation; you need to see how they work in the long run.
Tip 2: Refer, refer, refer. The world of drug development is a small one, and chances are someone you know, knows someone who knows someone at the CRO in question. Don’t be bashful, make the call and let your colleague know who you are considering. Best you find out before a contract is signed what the word on the street is.
Tip 3: Experience, experience, experience. No matter what anyone tells you people are human and the tendency to exaggerate or magnify their accomplishments is a natural inclination. When looking for a CRO make sure they are qualified in your area of expertise. The range of knowledge at a proficient CRO is often mindboggling but do your due diligence. If a CRO is only adept at Phase I/II trials and you are hoping they take you all the way to Phase IV, make sure you ask how they plan to get you there.
Tip 4: Size doesn’t matter. Small, medium or large, what CRO is the right one? Again, look at the qualifications of the team you want and who can best provide them. Sometimes a small CRO dedicated only to your project is the perfect fit. Sometimes a multi-national CRO able to provide a network of expertise around the globe will fit into your budget and development plan. Again, look at the “who” behind the logo and mission statement, and make sure you are buying a person with expertise, not a corporate image.
Tip 5: Blending your family. This may seem like the most silliest of points so far, but it is the most important. Make sure that all members of your team get a chance to speak to their counterpart on the CRO team. Nothing stirs up a blended family like insecurity and jealousy. Often Presidents, CEOs and Chairman of the Board are responsible for the final say in which CRO will get the project, which on a corporate level is a sound decision, but remember the dynamic. Co-operation between CRO and Sponsor is vital in getting both up to speed and a project completed. If a team member on either side feels threatened or put-out by the additions to their team the whole project can be derailed in a matter of ill-timed emails and sarcastic comebacks. Do your best to let your team know that a CRO is only an asset and not a commodity.
I was having coffee with a colleague the other day and we were discussing international clinic trials and the future of drug development when there seems to be a saturation of trials, investigators and new drug applications in North America. Being a proponent for trials in India, I suggested this country for their patient recruitment in a new oncology product.
“India!” he exclaimed, “you know what that stands for don’t you? I’ll Never Do It Again.” and then he chuckled.
I almost spit my coffee across the table, hearing for the first time the acronym for India. He may have a point, I have heard a lot of people have difficulty with the culture and attitude of India. Over the 15 years of auditing, monitoring and conducting trials in the country, I have not had one bad experience nor had my data questioned by the FDA or TPD.
“Thailand,” he said, “that’s the new hot spot! Drug Naïve patients, endless access to them and really good results and cheap…”
This of course sent me on a path of discovery. As a member of an innovative and progressive CRO, I thought, is Thailand the next country to host one of offices on a permanent basis? We have over 5 offices scattered across the globe and have participated in trials when the Sponsors indication showed promise in Thailand. I am always leery when any Sponsor uses the word “cheap” as attached to a clinical trial. The global market for clinical research by pharmaceutical and biotech companies approaches $110 billion in 2008 and approximately $12 billion of that went to CROs for outsources work. ARIANNE is small CRO that has created its own niche servicing clients in countries where the environment is favorable to the Sponsors development plan. I believe that Thailand is a country that can be cost effective and expeditious in clinical trials. When talking with our clients the benefits of working in Thailand include:
- Thailand is English speaking
- Well developed university and medical training network
- Government encourages and supports companies who want to start up in their country
- Thailand has served as sites for global biotech/pharmaceutical companies, WHO and international CROs
- As of 2007 Thailand was ranked seventh in Asia in number of clinical trials conducted
- Thailand’s population of 64 million has access to healthcare but only 4.4% have private insurance, this means a clinical trial is an alternative way for Thai citizens to gain access to treatment
- Thailand could also be the most suitable environment for Malaria, SARS, Dengue Fever or Avian flu
- Most of the investigators I researched had sites in medical schools and research centers where active IRBs were actively involved in the trials.
Navigating the regulatory pathway:
The regulatory procedure in Thailand is still a little confusing when approached with a North American frame of mind. The Thai regulatory is also called the FDA. The T-FDA as I will refer to it in this report is responsible for controlling the importation of new drugs from abroad for clinical trials. They are also involved with numerous international collaborations and initiatives which help to ensure product safety. The process is simple in design, but complicated in who has ultimate authority. For a drug company to conduct a trial in Thailand, they send a proposal to the Ethics Committee of the institute. When the Ethics Committee agrees with the trial they forward it to the T-FDA for approval. What is not mentioned in the guidelines is that the T-FDA have only approved eight medical schools as of 2008 as being allowed to apply to import a drug. This leads me to believe that a Sponsor must research their facility and investigator vigorously before moving forward.
From a regulatory point of view I believe that Thailand has moved in the right direction. The steps and procedures for basic ethical principles for human subject research are being put in place. Thailand has a Joint Research Ethics Committee, which is a private organization, is fully supportive in making Thailand the focal point for multi-centre clinical trials and working to ensure the rights of volunteers in studies are protected. I won’t say Thailand is the answer to all clinical trials looking for a certain population, but the 8 – 12 week approval time from conception to enrolment has great advantages.
I called my colleague and told him what I had discovered about Thailand and wished him well with his new clinical trial. There was a slight pause on the line and he asked rather sheepishly if our office in Bangalore was available.
Should similar standards be applied to clinical research conducted by academia and industry (Biotech, pharma etc)? Kit Howard recently expressed her thoughts on this topic.
http://www.clinpage.com/article/are_academics_competent/C12