The US Food and Drug Administration (USFDA) seems to have sent out a strong message to pharmaceutical companies in India on the need to adhere to a quality culture and on matters relating to data integrity. This was as part of 'Advanced GMP (good Manufacturing Practices' workshops that the US and European regulators conducted across four city of India between November 6th and 17th. Various presentations were made during these but one that needs particular mention is the USFDA paper titled: "Current Trends in Quality and Data Integrity Trends - Is it a Myth or tip of the iceberg?"
As is apparent from the paper, now posted on the website of the Indian Pharmaceutical Alliance, the number of warning letters issued by the Office of Manufacturing Quality of the USFDA to pharmaceutical companies has shot up and this is mainly on account of increase international warning letters (that is those outside of the US). And, in the international warning letters, India and China are two leading countries.
These warning letters used to average around 20 in a year in the calendar years 2013, 2014 and 2015. But these shot up to 43 in calendar year 2016. And so far 2017, seems to be no better, since already 35 warning letters have been issued.
Going by the numbers from this presentation, in 2017, out of about 45 warning letters in all, some 35 were international. In 2015, India accounted for the maximum number of warning letter. There was an improvement for India in 2016 and that year, China and others (those other than US, China and India) accounted for the maximum. However , in 2017, India and China are more or less on par in terms of warning letters received.
The key point therefore is that international account for a significant proportion of all the warning letters issued and while India was less than China in 2016, it is more or less equal in 2017.
What may be disturbing for pharma companies is the summary of the findings that the agency has arrived at based on the recent warning letters. For instance, it points out:1, Releasing failing product as if it had passed.2, Testing into compliance (in other words read: you keep on testing till you get a positive result)3, Not saving electronic or hard copy data that would confirm the failing results (which in a sense implies fabrication)4, Disabled audit trail feature.5, Inadequate out of specification investigation.6, Inadequate CAPAs (Corrective and Preventive Action).7, Root cause lacking scientific evidence.
As is apparent, the points one to four seem the findings but the rest from points 5 to 7 seem like analysis and remedial action. Next, the most cited observations are also listed with the section numbers also and here, Take two observations for example: 1, section 211.22(d): The responsibilities and procedures applicable to the quality control unit are not in writing or fully followed;2, section 211.160 (b): Laboratory controls do not include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures.
But it is really the pointers on why it feels these happen that need mention. Of the six pointers, two have been highlighted as these attribute the reasons to1, immature quality culture.2, Investigation focused on giving any explanation that may work, and not on what caused the problem in order to prevent recurrence and predict outcome.
Last but not the least, there is mention of symptoms and foundation problems. The symptom is that companies may be driven by production goals. One of the foundational problems cited is: 'lacking understanding of science.' Bad behaviour in terms of poor culture quality has also been pointed.
Ask Indian companies on what they think of these and while no one is willing to comment or get quoted, some felt that these are what the USFDA is finding world wide and not just in India. Others felt these need to be perhaps seen as a warning letters issued based on the conclusions that these might have happened and that it is now for the companies to prove that it has not happened. While some others felt, these are concerns which may not necessarily mean all have them. All were however agreed that these are the expectations of the regulator and companies have no option but to satisfy them and therefore move in the direction of what is expected. Also, some felt it also goes to show that it is not as if US companies are doing any better because the points listed out are for all the warning letters issued by the US regulator.
But at the end of it all, the key point remains that it is important for the US regulator and especially in India. Take one statistic that does the round in the pharma circles is that typically of the total number of ANDA applications that the USFDA receives in a month, about 50 per cent would be from India. In this respect, India is ahead of China, the other important hub for pharmaceuticals.But that is not to say, it is the only reason. As the presentation pointed out, the big worry is that the cases of non-adherence to some of the quality norms have also increased. There are some recurring citations and there are newer challenges too that need to be kept in mind.
In all, the workshops attracted some 400 odd participants all across four cities - Chandigarh, Ahmedabad, Goa and Hyderabad and these numbers also included some 100 odd domestic regulators, who also took part in these workshops. The goal of the meetings, organized by the Indian Pharmaceutical Alliance, but open to all pharma companies and not just its own members, was to educate people directly involved in various companies in India on issues around gaps in meeting global quality and monitoring requirements.
The regulators present at these workshops were from the US Food and Drug Administration's (US FDA), the UK Medicines and Healthcare Products Regulatory Agency (UK MHRA), the European Medicines Agency (EMA) and off course the India's Central Drugs Standard Control Organisation (CDSCO) and all seem focused on the need to adhere to better quality culture.
Statement from FDA Commissioner Scott Gottlieb, M.D., on steps to promote development of generic versions of opioids formulated to deter abuse:
As we continue to confront the staggering human and economic toll created by opioid abuse and addiction, we’re focused on taking actions that reduce the scope of new addiction by decreasing unnecessary exposure to opioids. At the same time, we also must take steps to help those with acute and chronic pain who need access to medicines, including opioids, get access to improved alternatives. Until we’re able to find new non-opioid forms of pain management for those who need treatment for pain, it’s critical that we also continue to promote the development of opioids that are harder to manipulate and abuse, and take steps to encourage their use over opioids that don’t offer any form of abuse deterrence.
Opioids with abuse-deterrent formulations (ADFs) are intended to make certain types of abuse, such as crushing a tablet to snort or dissolving a capsule to inject, more difficult or less rewarding. To date, the U.S. Food and Drug Administration has approved 10 opioid drugs with these properties. But their uptake has been slow among doctors who are treating patients in pain. The reason for their more limited use is likely multifold. We know there can be a learning curve that comes with new technologies. Some prescribers may not be aware of the existence of these drugs, or may be uncertain of when to prescribe the abuse-deterrent versions. But we also know a significant barrier to use can be price. Because these new formulations are currently only available as brand-name products, they’re inherently more expensive than the numerous non-abuse deterrent formulations that are also available in generic formulations. Transitioning from the current market, dominated by conventional opioids, to one in which most opioids have abuse-deterrent properties, holds significant promise for a meaningful public health benefit. But to transition this market more quickly to the ADFs, and consider permanently withdrawing the older formulations that lack abuse-deterrent features in the event these products were judged to be less safe ‒ there are a number of factors we must consider. One of the factors that the FDA would consider relates to generic access. We must have the potential to improve access to the newer formulations, for appropriately selected and monitored patients, through the introduction of generic competitors.
In order to support this transition and encourage advancements in this area, today the FDA issued a final guidance to assist industry in their development of generic versions of approved ADF opioids. This guidance includes new recommendations about the type of studies companies should conduct to demonstrate that the generic drug is no less abuse-deterrent than its brand-name counterpart. We’re also taking additional steps beyond the new guidance to help developers of generic ADFs navigate the regulatory path to market as quickly as possible and make the review process more efficient and predictable. For example, we’re developing appropriate, improved testing methodologies for evaluating complex features like abuse deterrence for both brand name (innovator) and generic opioid drug products. In addition, we’re also taking a flexible, adaptive approach to the evaluation and labeling of ADF opioids.
These efforts also include the development of new tools for expediting the generic development of complex products. The same features that make drugs hard to manipulate and abuse also make these formulations more complex, and therefore harder to develop generic versions of. To provide a more efficient pathway for the generic entry of these and other complex formulations, the FDA is advancing new review policies. For example, the new guidance will now assist generic drug developers who meet with the agency to discuss scientific and regulatory issues before submitting their applications. These meetings will enable the FDA to clarify the agency’s expectations early in the development process with the goal of reducing the time it takes to obtain approval. We’ll be taking additional steps to facilitate the efficient entry of complex generic drugs in the near future.
Together, all of these efforts are aimed at creating a more robust path for applicants who plan to develop and seek approval of generic ADF opioids.
Our goal is, when the use of any opioid drug product is appropriate, to make prescribing of these new formulations more commonplace. But let us be clear on one point. While these innovative formulations are designed to make it harder for people to manipulate the opioid drug so they can’t be abused, it’s important that prescribers and patients understand that these drugs are not “abuse-proof,” and they do not prevent addiction, overdose, or death. To address these issues, among other steps, we’re currently conducting a study to evaluate whether the nomenclature we use to describe these drugs, by labeling them “abuse deterrent,” is accurately conveying their benefits.
We also recognize that the science of abuse deterrence is relatively new. Both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving. That’s why we’re also focusing our efforts on determining how effective the current abuse-deterrent products are in the real-world setting and better understanding the attitudes and beliefs of health care professionals and those who are prescribed these products.
Further, all of these steps shouldn’t be mistaken as an effort that will encourage more opioid use. Our goal is to decrease the rate of new addiction, and thus any unnecessary legitimate and especially illicit use of opioids. Rather, this is an effort designed to encourage the shift – only when opioids are clinically appropriate ‒ from existing, easily abused products to those that are harder to manipulate.
This final guidance is one piece of the FDA’s ongoing work aimed at finding solutions to combat the opioid crisis. This effort must include treatments for those who are already addicted. That’s why we are also focusing new efforts on the development and promotion of medication-assisted treatments for addiction. As we balance the need to effectively treat pain with the public health emergency related to opioid addiction, we must find creative ways to prevent new cases of abuse and addiction.
The FDA, an agency within the U.S. Department of Health and Human Services, promotes and protects the public health by, among other things, assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
[Courtesy: with inputs from: http://www.businesstoday.in/sectors/pharma/usfda-delivers-strong-message-to-pharma-companies-on-quality-culture-data-integrity/story/264472.html]