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Worldwide inefficiencies in drug approval processes are proving disastrous for people living with TB and other diseases

By Erica Lessem

Access to safe and effective tuberculosis (TB) medicines depends greatly on efficient and stringent regulatory review, without which improved health outcomes are delayed. When it comes to evaluating new medicines, regulatory authorities have to balance multiple interests. They must strive to protect the public from harmful products, prevent ineffective drugs from entering the market, and ensure that patients have access to all necessary therapies.

Most regulators worldwide are poorly equipped to manage the delicate balancing act required to rapidly yet rigorously review new products to determine their safety, efficacy, and quality. And patients, doctors, and programs—as well as pharmaceutical entities, with large financial interests in the market entry of their products—are stuck along with them as they try to navigate this middle channel. Underfunded, and often mired in political controversies, regulatory agencies tend to lack the resources and power to efficiently and appropriately regulate medicines. This is especially true for TB. After an initial boom in the middle of the 20th century, decades of inactivity in research and development in TB have left regulators without experience or expertise in evaluating new treatment options with the potential to improve the lengthy, often toxic cures developed 50 years ago.

China’s Food and Drug Administration (FDA), rife with regulatory inefficiencies, has an average review time of six to eight years. In addition to the standard challenges of bureaucracy, inefficiencies, and lack of resources, the Chinese regulatory system is stymied by political backlash. After untested, tainted, and dangerous products passed through the Chinese FDA with bribes and corruption, causing several international scandals concentrated in 2007–2008, the country’s leadership attempted to show they were confronting product safety lapses by executing the Chinese FDA regulator (in 2007). In the aftermath of such a ghastly crackdown, it is much safer politically to let new drug approvals pile up rather than risk letting shoddy products through.

At the end of 2014, over 18,500 drugs were waiting for approval in China. Included in this massive list is bedaquiline, a critically important new drug for treating multidrug-resistant TB (MDR-TB) for people without other safe, effective treatment options. Bedaquiline was initially filed with both the Chinese and U.S. FDA in 2012. The U.S. FDA—a stringent regulatory authority—approved bedaquiline later that year. The Chinese FDA, in contrast, waited to review bedaquiline, along with other drugs, under what was referred to as the “modified” International Multi-Center Trials framework, and ultimately placed them on hold in the fall of 2013. The Chinese FDA, undergoing bureaucratic overhauls, ultimately requested resubmission, which bedaquiline’s sponsor, Janssen, did in September 2014. The drug has since been approved in Europe, India, Peru, the Philippines, Russia, South Africa, and South Korea but is still not approved in China. A linked submission to conduct a phase III trial of bedaquiline is also awaiting concurrent review and approval. Frustratingly, the Chinese FDA also lacks a legal or regulatory framework for several key pre-approval mechanisms such as compassionate use or expanded access trials (see table) that could serve as stopgap measures. Thus, bedaquiline is still not available to the over 18,000 patients each year there in need.

Promisingly, China’s State Council has recently announced that the Chinese FDA is reforming its approval system. It joined the International Coalition of Medicines Regulatory Authorities—indicating readiness to accept data from global clinical trials when approving new drugs—and will allow overseas drug makers to request expedited review for drugs that address unmet needs for HIV and other serious infectious diseases (as well as cancer and rare diseases). The Chinese FDA also agreed that, by 2018, every application would be approved or rejected within a certain time limit.

In a less gruesome case, India, the country with the largest national burden of MDR-TB, has overly cumbersome requirements to get new drugs and research approved through its Drug Controller General of India (DCGI) due to political controversies. A 2004 amendment to the Drugs and Cosmetics Act intended to liberalize the conduct of global drug trials in India led to the DCGI’s essentially acting as a facilitator for industry rather than a regulator. In 2013, the Indian Supreme Court ruled that the Central Drug Standard Control Organization under the DCGI failed to protect the rights of trial participants. The backlash from this well-intended ruling crippled further research and drug approvals in India by (for example) discouraging placebo-controlled and investigational product trials and those with foreign sponsors. Neither bedaquiline’s nor delamanid’s phase III trial has received approval in India despite the very large TB burden and abundance of research institutions that could serve as trial sites. The DCGI did manage to approve bedaquiline in mid-2015, two years after Janssen filed for its approval in May 2013. In the meantime, just a handful of patients have been able to get the drug under compassionate use.

Clearly, regulatory inefficiencies place patients affected by TB and other diseases at great risk of serious morbidity, disability, death, and transmission while they wait for effective, safe treatment options. These inefficiencies also further discourage pharmaceutical companies—already reluctant due to the trouble and expense of preparing dossiers in multiple formats and languages in countries where they are unlikely to make a large profit—from filing for registration widely. Yet widespread registration of new drugs is the only sustainable way to provide broad and long-term access (see table), and generally only originator companies have sufficient data, expertise, and resources to do so. Indeed, drug sponsors have an ethical obligation, as outlined in the Critical Path to TB Drug Regimen’s Good Participatory Practice Guidelines for TB Drug Trials, to develop posttrial access plans, particularly for the countries and communities where trials are conducted. For example, in the case of its TB drug, delamanid, Otsuka is in gross violation of this principle by having registered delamanid only in Europe, Japan, and Korea—countries where few people with MDR-TB live—despite having conducted registrational trials in countries with much larger MDR-TB burdens such as Peru, the Philippines, and South Africa.

For new and repurposed TB drugs to be developed and reach those who most need them, functional and transparent regulatory systems are key. Regulatory authorities need to be funded, staffed, and empowered to rapidly and thoroughly review applications for both research and marketing approval. Advocates should call for sustainable funding and improvements for their regulatory systems.

Global regulatory authorities should harmonize regionally to facilitate broader registration without jeopardizing quality. This could entail creating a single overarching regulatory agency for a given region or group of countries, meaning that study and product sponsors would need to file only one application (in one language, with one format, one list of requirements, and one set of queries to which to respond). This harmonization could be useful in expediting reviews while maintaining their rigor, since countries could pool financial and human resources and expertise to create a more efficient and knowledgeable regulatory infrastructure. By making the regulatory process simpler and more affordable for applicants, and pooling markets for products or demand for research across several countries, it could also help attract filings to countries that companies might otherwise overlook because of small or unprofitable markets or language barriers. Originator companies still need to widely register TB drugs in a range of high-burden countries and with stringent regulatory authorities—first and foremost in countries where trials were conducted.

Equally important is the ability of the public to track and provide input into the regulatory process. The U.S. FDA—while facing challenges of its own—has sound policies and procedures in place. These include clear timelines for responding to and making decisions on new drug and research applications, public hearings to solicit input prior to accelerated drug approvals, and public postings of key data submitted for new drug applications prior to and post approval. Activists worldwide should call for similar accountability and transparency from their regulators.

In the interim, activists, patients, doctors, and TB programs can use a range of strategies—from compassionate use to import waivers to operational research protocols—to maximize access to new and repurposed drugs or treatment regimens that have been validated elsewhere but may not yet be approved for marketing in a given country.•

Strategies for Using Regulatory Mechanisms for Drug Access

Mechanism Stage of Development Key Features Examples of Use for TB Drug Access

Compassionate use

During phase II (upon evidence of preliminary safety/signs of efficacy)
  • Pre-approval access mechanism
  • Doctor initiates request on behalf of individual patient
  • Drug sponsor must medically approve each individual case;  provides drug free of charge
  • National regulatory authority must permit import of drug (legal mechanism for pre-approval import must exist)
Compassionate use initiated for bedaquiline in 2011 after topline results from pivotal phase IIb trial showed preliminary favorable benefit/risk profile

Expanded access

During phase II (upon evidence of preliminary safety/signs of efficacy)
  • Pre-approval access mechanism
  • Alternative to compassionate use in countries lacking legal mechanism (e.g., Lithuania, Moldova, Russia)
  • Structured like clinical trial but without placebo arm or randomization (and sometimes without efficacy endpoints)
Expanded access trials for bedaquiline in Lithuania and Russia (note: similar application in China denied due to lack of efficacy outcomes/placebo arm)

Accelerated approval

After phase II (using surrogate endpoints)
  • Approval mechanism
  • Conditional upon completion of full phase III studies and other postmarketing requirements
  • Balances earlier access with need for confirmatory evidence from large-scale randomized clinical trials
  • Not all countries have an accelerated approval mechanism
U.S. Food and Drug Administration approval of bedaquiline (2012)

European Medicines Agency approval of bedaquiline and delamanid (2014)

Full approval

After phase III (using traditional, patient outcome endpoints)
  • Most durable way to secure widespread access


U.S. Food and Drug Administration approval of rifapentine for the treatment of latent TB infection (2014)

Import waivers

Postapproval (for drugs not yet registered in country of interest)
  • Usually granted for only limited time or for use in limited settings
  • Best as a temporary solution while full registration is pending
  • Useful strategy for new drugs approved by stringent regulatory authorities elsewhere or for a different indication, or for quality-assured generics that are not yet registered in a country
South African Medicines Control Council granted waiver to Médecins Sans Frontières for Hetero’s then unregistered generic linezolid due to prohibitive price of originator product


Operational research study

Pre- or postapproval (for drugs/regimens not yet registered in country of interest or experimental new regimens)
  • Can have longer or wider reach than import waivers
  • Has built-in advantage of gathering data
  • Best used while full registration for a drug is pending
  • Requires designing (or modifying template for) and submitting full research protocol, so still not ideal as long-term solution
  • Useful strategy for new drugs approved by stringent regulatory authorities elsewhere or for a different indication, or for new treatment strategies still in development using existing drugs
Several countries are using a shortened (9-month) MDR-TB regimen of existing drugs in programmatic settings under operational research protocols while results from the STREAM phase III clinical trial of this regimen are pending

Indonesia and Vietnam are rolling out bedaquiline, which is not yet approved in either country, under operational research protocols

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