Medicines and Monza: hazards of the fast track

Autodromo Nazionale Monza is a famous fast track. It has also been the place of many injuries and deaths. Just like motor racing, drug development can be dangerous ̶ go too fast and there may be disaster.
In drug regulation a fast track approval process aims to accelerate the availability of medicines on the market. There is a desire to provide new medicines quickly to patients with serious illnesses. However, there are enormous rewards for manufacturers who drive their products onto a fast track to win the race to market their products ahead of their competitors.

American fast tracks

The US Food and Drug Administration (FDA), in addition to its program for orphan drugs, has four fast tracks. Drugs can qualify for more than one track. While the accelerated approval track and priority reviews aim to expedite registration, the breakthrough therapy and fast-track designations help in drug development.

Fast track

The first of the fast tracks opened in 1988.This track emphasises early communication between the FDA and the drug company. It enables companies to have a ‘rolling review’ of their drugs. The companies submit information as it becomes available, rather than submitting data after all the clinical trials are completed.

Priority review

This track opened in 1992 around the time when new drugs for HIV infection were emerging. The FDA will give a drug a priority review if there is evidence of improvement in the diagnosis, prevention or treatment of a serious condition. A priority review can also be given if safety is improved. The FDA aims to make a decision about the drug in six months, rather than the usual ten months. This is the track most commonly used by drug companies to get their products approved quickly.

Accelerated approval

Some drugs have beneficial effects on surrogate outcomes. The FDA can accelerate the approval of a drug, based on surrogate outcomes, if there is an unmet clinical need for the treatment of a serious condition.

Breakthrough therapy

If there is preliminary clinical evidence that a drug is better than other treatments for a serious condition, it may be designated as a breakthrough therapy. The FDA will expedite the approval process and also give guidance on an efficient drug development program.

Canadian fast-track

Health Canada can give a priority review to drugs for serious illnesses if there is no other treatment available in Canada or the drug is a significant improvement. The target for a priority review is 180 days rather than the usual 300 days.

European fast track

Drugs that are of major interest to public health or therapeutic innovations can be given an accelerated assessment by the European Medicines Agency. The Committee for Medicinal Products for Human Use (CHMP) can reduce the time to review a marketing application to 150 days. A recent example is the accelerated approval of idarucizumab to meet the need for an antidote to the anticoagulant effects of dabigatran.

Australia

At present there is no fast-track in Australia. It has been proposed that approval of a drug could be expedited if the FDA has designated it as a breakthrough drug.

Speeding up

There is evidence that the number of drugs on fast tracks is increasing. A study in the USA found that, between 1987 and 2014, 774 new drugs were given expedited approval and there was a significant annual increase in the number of drugs in expedited programs.¹
The rapid approval of new drugs for cancer has been called ‘Drug development on speed’.² Between 2002 and 2012, the FDA approved 65 anticancer drugs for 127 indications. Most of these approvals were based on endpoints other than overall survival. Some drugs were approved even though they had no statistically significant effect on overall survival. For the 42 indications with accelerated approval 79% were based on response rates.³
The studies used for fast-track approvals may be small, non-randomised, phase II clinical trials. These can have a high statistical error rate. This may mean that the efficacy of the study drug appears greater than it really is. The error might only be detected if there is a subsequent phase III clinical trial, but this may be difficult to organise if the drug has already been marketed as a result of an accelerated approval process.²
If a drug approval is based on preliminary data, some of the cost of gathering more data is passed to health systems. This also means that the patients will probably be treated without the close supervision they have in pre-marketing trials. It is a paradox that fast-track approval may not reduce disparities in health care.⁴

Safety

A problem with fast-track approvals is that the number of patients treated is likely to be small and the duration of treatment may be short. This means that infrequent or long-term adverse effects may not be detected. The adverse effects only emerge after the new drug is approved and used without the limitations of clinical trial protocols.
Several studies have confirmed that drugs which are approved rapidly are likely to have safety problems. This risk is higher than for drugs approved at the usual speed.
A review of 434 new drugs approved in Canada between 1995 and 2010 found 19.4% had subsequent safety problems. For the 112 drugs which had a fast-track approval the probability of a serious safety issue was 34.2%.⁵
An analysis of 96 anticancer drugs approved by the FDA included 58 with priority reviews and 29 with accelerated approvals. A revision rate was calculated by dividing the number of revisions to the product label by the number of months the drug had been on the market. The revision rate for drugs with a priority review was 5.14 compared with 2.59 for drugs that were not given a priority review. Accelerated approval drugs had a revision rate of 7.15 compared with 3.39 for non-accelerated approvals.⁶
There are several examples of drugs which have crashed after negotiating a fast-track approval.

Ponatinib

Ponatinib underwent an accelerated approval process and was approved by the FDA for leukaemia in 2012. This decision was largely based on an unpublished phase II trial. Less than a year later the marketing of ponatinib was halted. As more data were being collected it emerged that the drug increased the risk of thrombosis. There had been no reports of arterial thrombosis in the preliminary data, but longer term follow up reported adverse vascular events in 48% of patients.⁷
The suspension of marketing was only for a few weeks. Ponatinib returned to the market with a narrower indication.

Alosetron

Alosetron is a 5HT3 receptor antagonist for the treatment of irritable bowel syndrome. Although this was not a life-saving treatment it was put on the fast-track to approval by the FDA. There was some concern about the adverse effects of alosetron, but it was marketed in the USA in 2000.
Within months there were post-marketing reports of severe complications such as ischaemic colitis. The company voluntarily withdrew the drug from the market, however in 2002 the FDA recommended that it be re-marketed with more restrictive indications.⁸

Rofecoxib

The COX-II inhibitors held the promise of pain relief without the gastro-intestinal adverse effects of other non-steroidal anti-inflammatory drugs. Rofecoxib was given a fast-track approval in countries such as Canada. It was approved in 1999.
By 2004 there was evidence associating rofecoxib with cardiovascular adverse effects including deaths. Rofecoxib was withdrawn from the world-wide market. Subsequent analysis revealed that the regulators had information about the increased risk of cardiovascular events long before rofecoxib was withdrawn.⁹

Troglitazone

The fast-track review of troglitazone was completed by the FDA within six months and it was approved in early 1997. A few months later troglitazone was also approved in Britain for the treatment of diabetes. Soon cases of liver failure were being reported and before the end of 1997 troglitazone had been withdrawn in Britain. It was not withdrawn in the USA until 2000.¹⁰

Gefitinib

After an accelerated approval process gefitinib was approved for the treatment of lung cancer in the USA. Post-marketing studies failed to show any clinical benefit. An application to market the drug in Europe was withdrawn and in the USA no new patients were allowed to start treatment. ¹¹
There is now greater understanding of the genetics of lung cancer. Gefitinib is again available in the USA, Europe and many other countries, but only for patients with particular mutations.

EMA versus FDA

Most of the literature which analyses the hazards of fast tracks involves the FDA. On average the approval of a new drug takes six months longer in Europe than in the USA. One reason for this is that most anticancer drugs in the USA are given a priority review.¹² Whether a new drug first appears in the USA or Europe also depends on when a new drug application is made.
An Italian-led study found that the regulatory agency which was first to approve a drug imposed less restrictions than the agency that was second. It also found differences in the decisions of the FDA and EMA over the same drug. For example, bevacizumab can be used in Europe as part of the management of patients with breast cancer. The FDA gave bevacizumab accelerated approval, but later revoked this indication because the potential harms outweighed the benefits.¹³

Pharmacovigilance

If drugs are to be approved more rapidly and at an earlier stage of their development, there is a need for more post-marketing surveillance. This includes confirming efficacy as well as monitoring for emerging adverse effects.
Regulatory agencies can approve risk management plans to monitor drugs after they are marketed. It is important to ensure that these plans are implemented and any additional trials are carried out. In April 2016 the FDA announced it was withdrawing its approval of lutropin. This drug had been given accelerated approval in 2004 with a requirement for post-marketing trials, however these studies were not done.¹⁴
A recent review of the performance of the FDA found that the agency struggled to track the safety of drugs which had been rapidly approved. Data need to be complete, accurate and timely. The review of the FDA found that information about post-marketing studies was often inaccurate, or out of date.¹⁵ It is also important that any pharmacovigilance system has sufficient numbers of trained staff to analyse the data.

Conclusion

A fast-track approval process can give patients earlier access to new drugs. However, it also gives them earlier exposure to harm. As some of the risks of drug development are being transferred to patients, it is important that they are informed of the hazards of fast tracks.
In the USA drugs can be given an expedited approval even if they are not a major advance. This seems to be an unnecessary risk, which Europe has largely avoided. Countries, such as Australia, need to be cautious if they are going to give marketing approvals based on the decisions of the FDA.¹⁶
It is important that documents such as the Statement of Product Characteristics state when a drug has been approved on preliminary data. There also needs to be ongoing evaluation of drugs which have been approved on a fast track. This will mean more resources for post-marketing surveillance, especially as adverse effects may take years to emerge.
Fast tracks can be exciting, but accelerating too fast can cause a crash.